Is AFM p.Arg434Ser (c.1302G>C) pathogenic?

AFM p.Arg434Ser (c.1302G>C) is classified Uncertain significance in AFM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.1515); Ultra-rare (popmax 0.0602%, eas).

How common is AFM p.Arg434Ser (c.1302G>C) in the general population?

AFM p.Arg434Ser (c.1302G>C) is ultra-rare (popmax 0.0602%, eas) (gnomAD).

What do computational predictors say about AFM p.Arg434Ser (c.1302G>C)?

AlphaMissense predicts likely benign (score 0.1515) — an in-silico prediction, not a clinical call.

AFM p.Arg434Ser

c.1302G>C · rs754857165 · VCV2218743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1515 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0602%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1515	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -5.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.19	GERP -3.3
Regional constraint	o/e 1.10	unconstrained · MANE · 21 kb · p 0.0081 · regional, not allelic
Overall
CADD	1.116	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 0.0602% East Asian · 27/44,832 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00192% 31/1,611,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0602%	1,660
Remaining individualsnot grpmax-eligible	0.00641%	15,598

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.Arg434Ser
Coding: c.1302G>C
MANE Select: NM_001133
dbSNP: rs754857165
Type: single nucleotide variant
Location: chr4:73499126 (GRCh38)
Gene constraint: LOEUF 1.44 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 434: a disulfide bond; 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.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-arg434ser (accessed [today's date]).

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