Is ANKRD12 p.Val581Ala (c.1742T>C) pathogenic?

ANKRD12 p.Val581Ala (c.1742T>C) is classified Uncertain significance in ANKRD12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.0964); Ultra-rare (popmax 0.0128%, nfe).

How common is ANKRD12 p.Val581Ala (c.1742T>C) in the general population?

ANKRD12 p.Val581Ala (c.1742T>C) is ultra-rare (popmax 0.0128%, nfe) (gnomAD).

What do computational predictors say about ANKRD12 p.Val581Ala (c.1742T>C)?

AlphaMissense predicts likely benign (score 0.0964) — an in-silico prediction, not a clinical call.

ANKRD12 p.Val581Ala

c.1742T>C · VCV4100985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0964 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0128%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0964	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -6.83	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 1.2	GERP -0.57, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 37 kb · p 6.1e-10 · regional, not allelic
Overall
CADD	15.39	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 0.0128% European (non-Finnish) · 151/1,177,976 alleles

Filtering AF 0.0111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0105%

Overall 0.00964% 155/1,608,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0128%	7,801
Remaining individualsnot grpmax-eligible	0.00643%	15,554

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: ANKRD12
Protein: p.Val581Ala
Coding: c.1742T>C
MANE Select: NM_015208
Type: single nucleotide variant
Location: chr18:9255009 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 41.33

Full ANKRD12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD12 p.Ala1049Thr Uncertain significance ★ ⚠ same type
ANKRD12 p.Ala1393Val Uncertain significance ★ ⚠ same type
ANKRD12 p.Ala1479Val Uncertain significance ★ ⚠ same type
ANKRD12 p.Ala1572Val Uncertain significance ★ ⚠ same type
ANKRD12 p.Ala1752Gly Uncertain significance ★ ⚠ same type
ANKRD12 p.Ala1805Thr Uncertain significance ★ ⚠ same type
ANKRD12 p.Ala1814Glu Uncertain significance ★ ⚠ same type
ANKRD12 p.Ala2013Val 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/ankrd12-p-val581ala (accessed [today's date]).

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