Is ANKRD2 p.Asp42Val (c.125A>T) pathogenic?

ANKRD2 p.Asp42Val (c.125A>T) is classified Uncertain significance in ANKRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: ambiguous (0.4348); Ultra-rare (popmax 0.0182%, mid).

How common is ANKRD2 p.Asp42Val (c.125A>T) in the general population?

ANKRD2 p.Asp42Val (c.125A>T) is ultra-rare (popmax 0.0182%, mid) (gnomAD).

What do computational predictors say about ANKRD2 p.Asp42Val (c.125A>T)?

AlphaMissense predicts ambiguous (score 0.4348) — an in-silico prediction, not a clinical call.

ANKRD2 p.Asp42Val

c.125A>T · rs2540045586 · VCV3123918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4348 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4348	ambiguous
REVEL	0.169	moderately benign-leaning
SaProt	LLR -7.96	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 11 kb · p 0.092 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM D69V vs ClinVar D42V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0182% Middle Eastern · 1/5,490 alleles

Overall 0.000127% 2/1,573,726 alleles · ultra-rare exomes 2/1,421,480 · genomes 0/152,246 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0182%	5,490
South Asian	0.00117%	85,526

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.Asp42Val
Coding: c.125A>T
MANE Select: NM_001346793
dbSNP: rs2540045586
Type: single nucleotide variant
Location: chr10:97577837 (GRCh38)
Gene constraint: LOEUF 1.426 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.30
Residue 69 UniProt numbering: the 'may mediate interaction with pml, p53/tp53 and ybx1' 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.Ala128Val 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

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-asp42val (accessed [today's date]).

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