Is ANK1 p.Arg699Trp (c.2095C>T) pathogenic?

ANK1 p.Arg699Trp (c.2095C>T) is classified Uncertain significance in ANK1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-23). AlphaMissense: likely benign (0.2657); Very rare (popmax 0.00667%, afr); Associated with ANK1-related disorder.

What condition is associated with ANK1 p.Arg699Trp (c.2095C>T)?

ANK1 p.Arg699Trp (c.2095C>T) is associated with ANK1-related disorder (ClinVar).

How common is ANK1 p.Arg699Trp (c.2095C>T) in the general population?

ANK1 p.Arg699Trp (c.2095C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about ANK1 p.Arg699Trp (c.2095C>T)?

AlphaMissense predicts likely benign (score 0.2657) — an in-silico prediction, not a clinical call.

ANK1 p.Arg699Trp

c.2095C>T · rs760027398 · VCV1984117

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ANK1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2657	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -10.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,926 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00161% 26/1,613,666 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,985
European (non-Finnish)	0.0017%	58,989
Remaining individualsnot grpmax-eligible	0.0016%	62,466

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.Arg699Trp
Coding: c.2095C>T
MANE Select: NM_000037
dbSNP: rs760027398
Type: single nucleotide variant
Location: chr8:41706145 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 699: the '89 kda domain' region

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

Disease context

ANK1-related disorder

Similar variants

ANK1 p.Arg699Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ANK1 c.1801-17G>A Pathogenic/Likely pathogenic ★★ same condition
ANK1 p.Arg1053Ter Pathogenic ★★ same condition
ANK1 p.Arg1682Ter Pathogenic ★★ same condition
ANK1 p.Arg281Ter Pathogenic/Likely pathogenic ★★ same condition
ANK1 p.Arg286Ter Pathogenic ★★ same condition
ANK1 p.Ser1646Ter Pathogenic/Likely pathogenic ★★ same condition
ANK1 p.Trp1600Ter Pathogenic/Likely pathogenic ★★ 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/ank1-p-arg699trp (accessed [today's date]).

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