# NM_001010982.5(AFMID):c.607G>A (p.Val203Met)

https://sugi.bio/variant/afmid-p-val203met

## Summary

**AFMID p.Val203Met (c.607G>A)** is classified **Likely benign** in AFMID (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.108); Ultra-rare (popmax 0.02%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs779472218 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.02%, amr)

## For patients & families {#patients}

This is a change in the AFMID gene that is classified as likely benign — not considered disease-causing, 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 | [AFMID](https://sugi.bio/atlas/gene/AFMID/) |
| Protein change (HGVS p.) | p.Val203Met |
| Coding change (HGVS c.) | c.607G>A |
| MANE Select transcript | [NM_001010982](https://www.ncbi.nlm.nih.gov/nuccore/NM_001010982) |
| dbSNP | [rs779472218](https://www.ncbi.nlm.nih.gov/snp/rs779472218/) |
| Variant type | single nucleotide variant |
| Location | chr17:78205481-78205481 (GRCh38) |
| ClinVar | [VCV3093232](https://www.ncbi.nlm.nih.gov/clinvar/variation/3093232/) |

**All HGVS expressions:** `NC_000017.10:g.76201562G>A`, `NC_000017.11:g.78205481G>A`, `NM_001010982.5:c.607G>A`, `NM_001145526.3:c.607G>A`, `NM_001391999.1:c.607G>A`, `NM_001392000.1:c.309-122G>A`, `NM_001392001.1:c.468-465G>A`, `NM_001392002.1:c.382-465G>A`, `NM_001392003.1:c.316-465G>A`, `NM_001392004.1:c.277-465G>A`, `NM_001392005.1:c.381+581G>A`, `NM_001392006.1:c.309-465G>A`, `NM_001392007.1:c.259G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.108)
- REVEL 0.019 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -11.124 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP -4.157, GERP -3.15 — fast-evolving / accelerated position
- CADD: **PHRED 0.022**. 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 0.97** across the covering region of the MANE Select transcript (78,187,371–78,206,934), spanning 19,563 bp. Chi-square p 0.53. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.33 acceptor 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 **0.02%** (amr) · FAF95 0.0115% · FAF99 0.00898% · 12/59,992 in the highest group · 57/1,614,054 alleles overall — ultra-rare (popmax 0.02%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.02% | 4,999 |
| South Asian | 0.0121% | 8,281 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,497 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00676% | 14,803 |
| East Asian | 0.00223% | 44,892 |
| European (non-Finnish) | 0.0022% | 45,386 |

*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}

**AFMID** population constraint: LOEUF 1.018, pLI 5.3725e-11, missense-Z 0.43583. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.39, 92% of residues very-high.

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

*Describes the biological roles of AFMID (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Tryptophan catabolism](https://reactome.org/content/detail/R-HSA-71240) | electronic |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-12.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-08-12 |

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

## Similar variants {#similar}

Related AFMID variant pages (same residue, condition, or type): [AFMID p.Ala41Asp](/variant/afmid-p-ala41asp), [AFMID p.Arg238His](/variant/afmid-p-arg238his), [AFMID p.Arg35Gln](/variant/afmid-p-arg35gln), [AFMID p.Asn291Lys](/variant/afmid-p-asn291lys), [AFMID p.Asp247Asn](/variant/afmid-p-asp247asn), [AFMID p.Asp247Glu](/variant/afmid-p-asp247glu), [AFMID p.Asp247Val](/variant/afmid-p-asp247val), [AFMID p.Cys237Gly](/variant/afmid-p-cys237gly).

### 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 3093232). 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.*