Is ANXA3 p.Ser49Pro (c.145T>C) pathogenic?

ANXA3 p.Ser49Pro (c.145T>C) is classified Uncertain significance in ANXA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.7293); Very rare (popmax 0.01%, amr).

How common is ANXA3 p.Ser49Pro (c.145T>C) in the general population?

ANXA3 p.Ser49Pro (c.145T>C) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ANXA3 p.Ser49Pro (c.145T>C)?

AlphaMissense predicts likely pathogenic (score 0.7293) — an in-silico prediction, not a clinical call.

ANXA3 p.Ser49Pro

c.145T>C · VCV4641305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7293	likely pathogenic
REVEL	0.19	benign-leaning
SaProt	LLR -10.58	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 56 kb · p 0.82 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,010 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000411% 6/1,460,286 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: ANXA3
Protein: p.Ser49Pro
Coding: c.145T>C
MANE Select: NM_005139
Type: single nucleotide variant
Location: chr4:78579068 (GRCh38)
Gene constraint: LOEUF 1.244 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.34 · 2 PDB

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

Similar variants

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.Arg274Gln Uncertain significance ★ ⚠ same type
ANXA3 p.Arg274Pro 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-ser49pro (accessed [today's date]).

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