# NM_174912.4(FAAH2):c.1404T>C (p.Pro468=)

https://sugi.bio/variant/faah2-p-pro468

## Summary

**FAAH2 p.Pro468= (c.1404T>C)** is classified **Benign** in FAAH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2013-08-12). Common (popmax 76.4%, nfe) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs1367830 · 2 submitters · common (popmax 76.4%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the FAAH2 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FAAH2](https://sugi.bio/atlas/gene/FAAH2/) |
| Protein change (HGVS p.) | p.Pro468= |
| Coding change (HGVS c.) | c.1404T>C |
| MANE Select transcript | [NM_174912](https://www.ncbi.nlm.nih.gov/nuccore/NM_174912) |
| dbSNP | [rs1367830](https://www.ncbi.nlm.nih.gov/snp/rs1367830/) |
| Variant type | single nucleotide variant |
| Location | chrX:57448699-57448699 (GRCh38) |
| ClinVar | [VCV96551](https://www.ncbi.nlm.nih.gov/clinvar/variation/96551/) |

**All HGVS expressions:** `NC_000023.10:g.57475132T>C`, `NC_000023.11:g.57448699T>C`, `NG_013232.2:g.167023T>C`, `NM_001353840.1:c.1284T>C`, `NM_001353841.1:c.1194T>C`, `NM_174912.4:c.1404T>C`, `NR_148557.2:n.1376T>C`, `NR_148564.2:n.1376T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 76.4%, nfe) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.402, GERP 0.697, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.283**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.22 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **76.4%** (nfe) · FAF95 76.2% · FAF99 76.2% · 682,912/893,979 in the highest group · 854,552/1,207,169 alleles overall — common (popmax 76.4%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 90.1% | 1 |
| Finnish (not grpmax-eligible) | 82.7% | 1 |
| European (non-Finnish) (grpmax) | 76.4% | 1 |
| East Asian | 67.2% | 1 |
| Remaining individuals (not grpmax-eligible) | 64.6% | 2 |
| South Asian | 64% | 2 |
| Admixed American | 53.6% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 52.9% | 2 |
| Middle Eastern | 40.4% | 2 |
| African / African-American | 9.89% | 10 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}


Curated gene–disease validity (ClinGen):

- **X-linked complex neurodevelopmental disorder** — Disputed (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.08, 85% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of FAAH2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** FAAH2's established molecular role includes fatty acid amide hydrolase activity.


### Pathways affected {#pathways}

FAAH2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Arachidonate metabolism](https://reactome.org/content/detail/R-HSA-2142753) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** fatty acid amide hydrolase activity.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2013-08-12.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2013); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2013-08-12 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not specified, not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, AllHighlyPenetrant.

## Similar variants {#similar}

Related FAAH2 variant pages (same residue, condition, or type): [FAAH2 p.Pro468Ser](/variant/faah2-p-pro468ser), [FAAH2 c.1229-14A>T](/variant/faah2-c-1229-minus-14a-t), [FAAH2 p.Arg274=](/variant/faah2-p-arg274), [FAAH2 p.Arg42Trp](/variant/faah2-p-arg42trp), [FAAH2 c.742+5T>A](/variant/faah2-c-742-plus-5t-a), [FAAH2 p.Ala115Val](/variant/faah2-p-ala115val), [FAAH2 p.Ala157Asp](/variant/faah2-p-ala157asp), [FAAH2 p.Ala161Thr](/variant/faah2-p-ala161thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 96551). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*