Is ANK1 p.Ala399Val (c.1196C>T) pathogenic?

ANK1 p.Ala399Val (c.1196C>T) is classified Uncertain significance in ANK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-14). AlphaMissense: likely pathogenic (0.6972); Ultra-rare (popmax 0.0187%, sas).

How common is ANK1 p.Ala399Val (c.1196C>T) in the general population?

ANK1 p.Ala399Val (c.1196C>T) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about ANK1 p.Ala399Val (c.1196C>T)?

AlphaMissense predicts likely pathogenic (score 0.6972) — an in-silico prediction, not a clinical call.

ANK1 p.Ala399Val

c.1196C>T · rs753718191 · VCV1163300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6972	likely pathogenic
REVEL	0.375	indeterminate
SaProt	LLR -12.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	25.4	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,080 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00384% 62/1,613,734 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
Middle Eastern	0.0164%	6,084
East Asian	0.00446%	22,440
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00322%	31,052
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-American	0.00134%	74,896

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: ANK1
Protein: p.Ala399Val
Coding: c.1196C>T
MANE Select: NM_000037
dbSNP: rs753718191
Type: single nucleotide variant
Location: chr8:41718116 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 399: the '89 kda domain' region

Full ANK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANK1 p.Ala399= Conflicting classifications of pathogenicity ★ same residue
ANK1 p.Ala399Thr Uncertain significance ★ ⚠ same residue
ANK1 p.Ala399fs Likely pathogenic ★ same residue
ANK1 c.1305+1G>A Pathogenic ★★ same type
ANK1 c.1405-9G>A Pathogenic/Likely pathogenic ★★ same type
ANK1 c.1702-2A>G Pathogenic/Likely pathogenic ★★ same type
ANK1 c.1801-17G>A Pathogenic/Likely pathogenic ★★ same type
ANK1 c.1801-2A>T Likely pathogenic ★★ 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/ank1-p-ala399val (accessed [today's date]).

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