# NM_001528.4(HGFAC):c.331C>G (p.Pro111Ala)

https://sugi.bio/variant/hgfac-p-pro111ala

## Summary

**HGFAC p.Pro111Ala (c.331C>G)** is classified **Uncertain significance** in HGFAC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-23). AlphaMissense: likely pathogenic (0.8756); Very rare (popmax 0.00187%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00187%, nfe)

## For patients & families {#patients}

This is a change in the HGFAC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [HGFAC](https://sugi.bio/atlas/gene/HGFAC/) |
| Protein change (HGVS p.) | p.Pro111Ala |
| Coding change (HGVS c.) | c.331C>G |
| MANE Select transcript | [NM_001528](https://www.ncbi.nlm.nih.gov/nuccore/NM_001528) |
| Variant type | single nucleotide variant |
| Location | chr4:3443082-3443082 (GRCh38) |
| ClinVar | [VCV3857710](https://www.ncbi.nlm.nih.gov/clinvar/variation/3857710/) |

**All HGVS expressions:** `NC_000004.11:g.3444809C>G`, `NC_000004.12:g.3443082C>G`, `NM_001297439.2:c.331C>G`, `NM_001528.4:c.331C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8756)
- REVEL 0.522 (indeterminate)
- SaProt LLR -11.541 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.359, GERP 0.212, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.1**. 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.*
- Regional missense constraint: **o/e 1.12** across the covering region of the MANE Select transcript (3,442,002–3,449,416), spanning 7,414 bp. Chi-square p 0.00031. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.10**, donor gain **0.30**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.10**, donor gain **0.30**.
- Population frequency (gnomAD v4.1): grpmax **0.00187%** (nfe) · FAF95 0.00122% · FAF99 0.00104% · 22/1,178,636 in the highest group · 25/1,599,352 alleles overall — very rare (popmax 0.00187%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00187% | 53,574 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,190 |
| African / African-American | 0.00134% | 74,854 |
| South Asian | 0.0011% | 90,614 |

*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}

**HGFAC** population constraint: LOEUF 1.64, pLI 4.0417e-33, missense-Z -2.4994. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **111** lies in a disulfide bond; the fibronectin type-ii domain.

AlphaFold model confidence (whole protein): pLDDT 75.81, 38% of residues very-high.

**7 experimental structure(s)** (PDB): [1YBW](https://www.rcsb.org/structure/1YBW), [1YC0](https://www.rcsb.org/structure/1YC0), [2R0K](https://www.rcsb.org/structure/2R0K), [2R0L](https://www.rcsb.org/structure/2R0L), [2WUB](https://www.rcsb.org/structure/2WUB), [2WUC](https://www.rcsb.org/structure/2WUC).

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

*Describes the biological roles of HGFAC (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [MET Receptor Activation](https://reactome.org/content/detail/R-HSA-6806942) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-23.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-23 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related HGFAC variant pages (same residue, condition, or type): [HGFAC p.Ala121Pro](/variant/hgfac-p-ala121pro), [HGFAC p.Ala268Ser](/variant/hgfac-p-ala268ser), [HGFAC p.Ala274Thr](/variant/hgfac-p-ala274thr), [HGFAC p.Ala327Val](/variant/hgfac-p-ala327val), [HGFAC p.Ala328Val](/variant/hgfac-p-ala328val), [HGFAC p.Ala356Val](/variant/hgfac-p-ala356val), [HGFAC p.Ala424Pro](/variant/hgfac-p-ala424pro), [HGFAC p.Ala446Ser](/variant/hgfac-p-ala446ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3857710). 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.*