Is ANK2 p.Asp676Val (c.2027A>T) pathogenic?

ANK2 p.Asp676Val (c.2027A>T) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-01). AlphaMissense: ambiguous (0.3534); Very rare (popmax 0.00223%, eas); Associated with complex neurodevelopmental disorder.

What condition is associated with ANK2 p.Asp676Val (c.2027A>T)?

ANK2 p.Asp676Val (c.2027A>T) is associated with complex neurodevelopmental disorder (ClinVar).

How common is ANK2 p.Asp676Val (c.2027A>T) in the general population?

ANK2 p.Asp676Val (c.2027A>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ANK2 p.Asp676Val (c.2027A>T)?

AlphaMissense predicts ambiguous (score 0.3534) — an in-silico prediction, not a clinical call.

ANK2 p.Asp676Val

c.2027A>T · rs2495911542 · VCV3253483

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

complex neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.3534	ambiguous
REVEL	0.728	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ1.00 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Overall 6.2e-05% 1/1,614,050 alleles · very rare exomes 1/1,461,754 · genomes 0/152,296 · joint denominator

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: ANK2
Protein: p.Asp676Val
Coding: c.2027A>T
MANE Select: NM_001148
dbSNP: rs2495911542
Type: single nucleotide variant
Location: chr4:113282820 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 676: an α-helix

Full ANK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complex neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

ANK2 p.Asp676Glu Uncertain significance ★ ⚠ same residue
ANK2 p.Ala2754Val Uncertain significance ★★ ⚠ same condition
ANK2 p.Asn795Thr Uncertain significance ★★ ⚠ same condition
ANK2 p.Cys3244Arg Uncertain significance ★★ ⚠ same condition
ANK2 p.Gly673Val Uncertain significance ★★ ⚠ same condition
ANK2 p.Thr2271Ile Uncertain significance ★★ ⚠ same condition
ANK2 p.Thr697Arg Uncertain significance ★ ⚠ same condition
ANK2 p.Cys60Ter Uncertain significance same condition

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/ank2-p-asp676val (accessed [today's date]).

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