Is ANK1 p.Arg941Trp (c.2821C>T) pathogenic?

ANK1 p.Arg941Trp (c.2821C>T) is classified Uncertain significance in ANK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-04). AlphaMissense: likely pathogenic (0.7599); Ultra-rare (popmax 0.0154%, sas).

How common is ANK1 p.Arg941Trp (c.2821C>T) in the general population?

ANK1 p.Arg941Trp (c.2821C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about ANK1 p.Arg941Trp (c.2821C>T)?

AlphaMissense predicts likely pathogenic (score 0.7599) — an in-silico prediction, not a clinical call.

ANK1 p.Arg941Trp

c.2821C>T · rs375019877 · VCV2428922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7599 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7599	likely pathogenic
REVEL	0.571	indeterminate
SaProt	LLR -11.41	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 2.4	GERP -2.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	21.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% South Asian · 14/91,082 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00167% 27/1,613,392 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,506
East Asian	0.00223%	44,884
Finnishnot grpmax-eligible	0.00158%	63,426
African / African-American	0.00133%	74,938
European (non-Finnish)	0.000847%	117,999

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.Arg941Trp
Coding: c.2821C>T
MANE Select: NM_000037
dbSNP: rs375019877
Type: single nucleotide variant
Location: chr8:41696502 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 941: the zu5 1 domain

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

Similar variants

ANK1 p.Arg941Gln Uncertain significance ★ ⚠ 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
ANK1 c.1998+1G>T Likely pathogenic ★★ same type
ANK1 c.2296-1G>A 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-arg941trp (accessed [today's date]).

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