Is AFM p.Cys77Arg (c.229T>C) pathogenic?

AFM p.Cys77Arg (c.229T>C) is classified Uncertain significance in AFM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.8907); Very rare (popmax 0.000933%, nfe).

How common is AFM p.Cys77Arg (c.229T>C) in the general population?

AFM p.Cys77Arg (c.229T>C) is very rare (popmax 0.000933%, nfe) (gnomAD).

What do computational predictors say about AFM p.Cys77Arg (c.229T>C)?

AlphaMissense predicts likely pathogenic (score 0.8907) — an in-silico prediction, not a clinical call.

AFM p.Cys77Arg

c.229T>C · VCV4638760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8907	likely pathogenic · top 1% in AFM
REVEL	0.631	indeterminate
SaProt	LLR -14.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.4	GERP -1.6, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 21 kb · p 0.0081 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000933% European (non-Finnish) · 11/1,179,286 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,612,090 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AFM
Protein: p.Cys77Arg
Coding: c.229T>C
MANE Select: NM_001133
Type: single nucleotide variant
Location: chr4:73484349 (GRCh38)
Gene constraint: LOEUF 1.44 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 77: a disulfide bond; the albumin 1 domain; an α-helix

Full AFM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFM p.Ala100Val Uncertain significance ★ ⚠ same type
AFM p.Ala150Pro Uncertain significance ★ same type
AFM p.Ala241Val Uncertain significance ★ ⚠ same type
AFM p.Ala352Glu Uncertain significance ★ ⚠ same type
AFM p.Ala352Val Uncertain significance ★ ⚠ same type
AFM p.Ala397Thr Uncertain significance ★ ⚠ same type
AFM p.Ala397Val Uncertain significance ★ ⚠ same type
AFM p.Ala439Pro Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/afm-p-cys77arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown