Is ANKRD2 p.Ala128Val (c.383C>T) pathogenic?

ANKRD2 p.Ala128Val (c.383C>T) is classified Uncertain significance in ANKRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.87); Ultra-rare (popmax 0.0122%, nfe).

How common is ANKRD2 p.Ala128Val (c.383C>T) in the general population?

ANKRD2 p.Ala128Val (c.383C>T) is ultra-rare (popmax 0.0122%, nfe) (gnomAD).

What do computational predictors say about ANKRD2 p.Ala128Val (c.383C>T)?

AlphaMissense predicts likely pathogenic (score 0.87) — an in-silico prediction, not a clinical call.

ANKRD2 p.Ala128Val

c.383C>T · VCV4101914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.87 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.87	likely pathogenic
REVEL	0.769	pathogenic-leaning
SaProt	LLR -14.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 11 kb · p 0.092 · regional, not allelic
Overall
CADD	28.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A155V vs ClinVar A128V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0122% European (non-Finnish) · 142/1,161,370 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00996%

Overall 0.00957% 151/1,577,592 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0122%	8,179
Remaining individualsnot grpmax-eligible	0.00981%	10,195
African / African-American	0.00404%	24,736

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: ANKRD2
Protein: p.Ala128Val
Coding: c.383C>T
MANE Select: NM_001346793
Type: single nucleotide variant
Location: chr10:97578532 (GRCh38)
Gene constraint: LOEUF 1.426 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.30
Residue 128: the 'disordered' region

Full ANKRD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD2 p.Ala285= Benign ★★ same type
ANKRD2 p.Pro119Leu Benign/Likely benign ★★ ⚠ same type
ANKRD2 p.Pro6Arg Benign ★★ same type
ANKRD2 p.Ala10Val Uncertain significance ★ ⚠ same type
ANKRD2 p.Ala12Thr Uncertain significance ★ ⚠ same type
ANKRD2 p.Ala311Val Uncertain significance ★ ⚠ same type
ANKRD2 p.Arg100Pro Uncertain significance ★ ⚠ same type
ANKRD2 p.Arg155Gln 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/ankrd2-p-ala128val (accessed [today's date]).

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