Is ANXA9 p.Pro146Ala (c.436C>G) pathogenic?

ANXA9 p.Pro146Ala (c.436C>G) is classified Uncertain significance in ANXA9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.0468); Ultra-rare (popmax 0.0333%, amr).

How common is ANXA9 p.Pro146Ala (c.436C>G) in the general population?

ANXA9 p.Pro146Ala (c.436C>G) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about ANXA9 p.Pro146Ala (c.436C>G)?

AlphaMissense predicts likely benign (score 0.0468) — an in-silico prediction, not a clinical call.

ANXA9 p.Pro146Ala

c.436C>G · VCV4112982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0468 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0468	likely benign
REVEL	0.003	strongly benign-leaning
SaProt	LLR -5.67	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 -2.1	GERP -3.3
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 0.002 · regional, not allelic
Overall
CADD	0.186	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 0.0333% Admixed American · 20/60,008 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00979% 158/1,614,112 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,000
Remaining individualsnot grpmax-eligible	0.0176%	5,683
European (non-Finnish)	0.0103%	9,672
East Asian	0.00446%	22,443
African / African-American	0.004%	25,007

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: ANXA9
Protein: p.Pro146Ala
Coding: c.436C>G
MANE Select: NM_003568
Type: single nucleotide variant
Location: chr1:150984640 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.51

Full ANXA9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANXA9 p.Ala141Gly Uncertain significance ★ ⚠ same type
ANXA9 p.Ala199Ser Uncertain significance ★ ⚠ same type
ANXA9 p.Ala310Asp Uncertain significance ★ ⚠ same type
ANXA9 p.Arg239Gly Uncertain significance ★ ⚠ same type
ANXA9 p.Arg252His Uncertain significance ★ ⚠ same type
ANXA9 p.Arg295Cys Uncertain significance ★ ⚠ same type
ANXA9 p.Arg295Leu Uncertain significance ★ ⚠ same type
ANXA9 p.Arg300Leu 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/anxa9-p-pro146ala (accessed [today's date]).

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