Is AFM p.Arg279Ser (c.835C>A) pathogenic?

AFM p.Arg279Ser (c.835C>A) is classified Uncertain significance in AFM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely benign (0.2952); Ultra-rare (popmax 0.0326%, sas).

How common is AFM p.Arg279Ser (c.835C>A) in the general population?

AFM p.Arg279Ser (c.835C>A) is ultra-rare (popmax 0.0326%, sas) (gnomAD).

What do computational predictors say about AFM p.Arg279Ser (c.835C>A)?

AlphaMissense predicts likely benign (score 0.2952) — an in-silico prediction, not a clinical call.

AFM p.Arg279Ser

c.835C>A · VCV4248439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2952 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0326%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2952	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -4.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.051	GERP 0.62
Regional constraint	o/e 1.10	unconstrained · MANE · 21 kb · p 0.0081 · regional, not allelic
Overall
CADD	16.64	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 0.0326% South Asian · 29/88,842 alleles

Filtering AF 0.0233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0201%

Overall 0.00213% 31/1,454,424 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0326%	3,064
Middle Eastern	0.0165%	6,054
Remaining individualsnot grpmax-eligible	0.00161%	62,270

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.Arg279Ser
Coding: c.835C>A
MANE Select: NM_001133
Type: single nucleotide variant
Location: chr4:73488751 (GRCh38)
Gene constraint: LOEUF 1.44 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 279: the albumin 2 domain; an α-helix; the 'binding pocket for hydrophobic ligands' region

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

Similar variants

AFM p.Arg279Cys 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-arg279ser (accessed [today's date]).

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