Is AFM p.Pro493Arg (c.1478C>G) pathogenic?

AFM p.Pro493Arg (c.1478C>G) is classified Uncertain significance in AFM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: likely benign (0.1267); Ultra-rare (popmax 0.0146%, nfe).

How common is AFM p.Pro493Arg (c.1478C>G) in the general population?

AFM p.Pro493Arg (c.1478C>G) is ultra-rare (popmax 0.0146%, nfe) (gnomAD).

What do computational predictors say about AFM p.Pro493Arg (c.1478C>G)?

AlphaMissense predicts likely benign (score 0.1267) — an in-silico prediction, not a clinical call.

AFM p.Pro493Arg

c.1478C>G · rs767460010 · VCV2411355

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1267 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0146%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1267	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.014, phastCons 0.47
Regional constraint	o/e 1.10	unconstrained · MANE · 21 kb · p 0.0081 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0146% European (non-Finnish) · 172/1,179,950 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.0114% 184/1,613,902 alleles · ultra-rare exomes 175/1,461,722 · genomes 9/152,180 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0146%	6,860
Remaining individualsnot grpmax-eligible	0.0112%	8,925
African / African-American	0.00534%	18,730
Admixed American	0.00167%	59,982

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.Pro493Arg
Coding: c.1478C>G
MANE Select: NM_001133
dbSNP: rs767460010
Type: single nucleotide variant
Location: chr4:73500059 (GRCh38)
Gene constraint: LOEUF 1.44 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 493: the albumin 3 domain; an α-helix

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

Similar variants

AFM p.Pro493Ser Uncertain significance ★ ⚠ same residue
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

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-pro493arg (accessed [today's date]).

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