Is ANK1 p.Ala1553Val (c.4658C>T) pathogenic?

ANK1 p.Ala1553Val (c.4658C>T) is classified Uncertain significance in ANK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-19). AlphaMissense: likely benign (0.1757); Very rare (popmax 0.00936%, afr).

How common is ANK1 p.Ala1553Val (c.4658C>T) in the general population?

ANK1 p.Ala1553Val (c.4658C>T) is very rare (popmax 0.00936%, afr) (gnomAD).

What do computational predictors say about ANK1 p.Ala1553Val (c.4658C>T)?

AlphaMissense predicts likely benign (score 0.1757) — an in-silico prediction, not a clinical call.

ANK1 p.Ala1553Val

c.4658C>T · rs774117685 · VCV1441587

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1757 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00936%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1757	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -7.02	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 5.8	GERP -1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 23 kb · p 0.11 · regional, not allelic
Overall
CADD	23.8	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 0.00936% African / African-American · 7/74,770 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.0033% 53/1,604,164 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00936%	10,681
East Asian	0.00671%	14,911
European (non-Finnish)	0.00341%	29,344
South Asian	0.00222%	44,977
Admixed American	0.00168%	59,586

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.Ala1553Val
Coding: c.4658C>T
MANE Select: NM_000037
dbSNP: rs774117685
Type: single nucleotide variant
Location: chr8:41672792 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 1553: the '55 kda regulatory domain' region

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

Similar variants

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
ANK1 c.1998+1G>T Likely pathogenic ★★ same type
ANK1 c.2296-1G>A Likely pathogenic ★★ same type
ANK1 c.2296-2A>G Pathogenic/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-ala1553val (accessed [today's date]).

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