Is ANXA3 p.Arg274Pro (c.821G>C) pathogenic?

ANXA3 p.Arg274Pro (c.821G>C) is classified Uncertain significance in ANXA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.9856); Ultra-rare (popmax 0.0167%, amr).

How common is ANXA3 p.Arg274Pro (c.821G>C) in the general population?

ANXA3 p.Arg274Pro (c.821G>C) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about ANXA3 p.Arg274Pro (c.821G>C)?

AlphaMissense predicts likely pathogenic (score 0.9856) — an in-silico prediction, not a clinical call.

ANXA3 p.Arg274Pro

c.821G>C · rs771966889 · VCV2403776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9856 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9856	likely pathogenic · top 1% in ANXA3
REVEL	0.819	moderately pathogenic-leaning
SaProt	LLR -17.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 56 kb · p 0.82 · regional, not allelic
Overall
CADD	33.0	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 0.0167% Admixed American · 10/59,988 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000744% 12/1,612,946 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
Remaining individualsnot grpmax-eligible	0.0016%	62,438
European (non-Finnish)	8.48e-05%	1,179,266

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: ANXA3
Protein: p.Arg274Pro
Coding: c.821G>C
MANE Select: NM_005139
dbSNP: rs771966889
Type: single nucleotide variant
Location: chr4:78604308 (GRCh38)
Gene constraint: LOEUF 1.244 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.34 · 2 PDB
Residue 274: an α-helix

Full ANXA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANXA3 p.Arg274Gln Uncertain significance ★ ⚠ same residue
ANXA3 p.Ile219Asn Benign ★★ ⚠ same type
ANXA3 p.Ser19Asn Benign ★★ same type
ANXA3 p.Ala112Gly Uncertain significance ★ ⚠ same type
ANXA3 p.Ala24Val Uncertain significance ★ ⚠ same type
ANXA3 p.Arg123Lys Uncertain significance ★ ⚠ same type
ANXA3 p.Arg153Gln Uncertain significance ★ ⚠ same type
ANXA3 p.Arg53Trp 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/anxa3-p-arg274pro (accessed [today's date]).

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