Is ANKRD31 p.Ile993Val (c.2977A>G) pathogenic?

ANKRD31 p.Ile993Val (c.2977A>G) is classified Uncertain significance in ANKRD31 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.096); Rare (popmax 0.118%, nfe).

How common is ANKRD31 p.Ile993Val (c.2977A>G) in the general population?

ANKRD31 p.Ile993Val (c.2977A>G) is rare (popmax 0.118%, nfe) (gnomAD).

What do computational predictors say about ANKRD31 p.Ile993Val (c.2977A>G)?

AlphaMissense predicts likely benign (score 0.096) — an in-silico prediction, not a clinical call.

ANKRD31 p.Ile993Val

c.2977A>G · VCV4106204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.096 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.118%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.096	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -5.95	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	GERP -3.7
Regional constraint	o/e 0.92	unconstrained · MANE · 168 kb · p 0.00044 · regional, not allelic
Overall
CADD	1.663	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 0.118% European (non-Finnish) · 1,352/1,146,452 alleles

Filtering AF 0.113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.111%

Overall 0.0922% 1,416/1,536,482 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.118%	848
Remaining individualsnot grpmax-eligible	0.04%	2,499
Finnishnot grpmax-eligible	0.0329%	3,040
Admixed American	0.0255%	3,918
African / African-American	0.0137%	7,311
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,614
South Asian	0.00119%	84,018

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: ANKRD31
Protein: p.Ile993Val
Coding: c.2977A>G
MANE Select: NM_001372053
Type: single nucleotide variant
Location: chr5:75146434 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 43.08

Full ANKRD31 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD31 p.Arg1353Gln Benign ★★ same type
ANKRD31 p.Asn192Ile Benign ★★ same type
ANKRD31 c.1565-2A>G Pathogenic ★ same type
ANKRD31 p.Gln329Ter Pathogenic ★ same type
ANKRD31 p.Ala1011Asp Uncertain significance ★ ⚠ same type
ANKRD31 p.Ala1021Thr Uncertain significance ★ ⚠ same type
ANKRD31 p.Ala1294Thr Uncertain significance ★ ⚠ same type
ANKRD31 p.Ala1302Thr 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/ankrd31-p-ile993val (accessed [today's date]).

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