Is ANK1 p.Arg1255Cys (c.3763C>T) pathogenic?

ANK1 p.Arg1255Cys (c.3763C>T) is classified Conflicting classifications of pathogenicity in ANK1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-26). AlphaMissense: likely benign (0.2102); Ultra-rare (popmax 0.0317%, nfe); Associated with hereditary spherocytosis type 1.

What condition is associated with ANK1 p.Arg1255Cys (c.3763C>T)?

ANK1 p.Arg1255Cys (c.3763C>T) is associated with hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Arg1255Cys (c.3763C>T) in the general population?

ANK1 p.Arg1255Cys (c.3763C>T) is ultra-rare (popmax 0.0317%, nfe) (gnomAD).

How is Hereditary spherocytosis inherited?

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

What do computational predictors say about ANK1 p.Arg1255Cys (c.3763C>T)?

AlphaMissense predicts likely benign (score 0.2102) — an in-silico prediction, not a clinical call.

ANK1 p.Arg1255Cys

c.3763C>T · rs148275567 · VCV2439075

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2102 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spherocytosis type 1

Computational evidence

Protein change
AlphaMissense	0.2102	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -12.41	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 5	GERP -0.46, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	27.9	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 0.0317% European (non-Finnish) · 374/1,180,020 alleles

Filtering AF 0.029% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0279%

Overall 0.0309% 498/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.153%	653
European (non-Finnish)grpmax	0.0317%	3,155
Remaining individualsnot grpmax-eligible	0.0192%	5,209
East Asian	0.0178%	5,608
African / African-American	0.00667%	14,998
South Asian	0.0011%	91,074

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1255Cys
Coding: c.3763C>T
MANE Select: NM_000037
dbSNP: rs148275567
Type: single nucleotide variant
Location: chr8:41692743 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 1255: the 'upa domain' region

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

Disease context

hereditary spherocytosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary spherocytosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Germany)

Similar variants

ANK1 p.Arg1255His Uncertain significance ★★ ⚠ same residue
ANK1 c.1305+1G>A Pathogenic ★★ same condition
ANK1 c.1405-9G>A Pathogenic/Likely pathogenic ★★ same condition
ANK1 c.1702-2A>G Pathogenic/Likely pathogenic ★★ same condition
ANK1 c.1801-17G>A Pathogenic/Likely pathogenic ★★ same condition
ANK1 c.2296-1G>A Likely pathogenic ★★ same condition
ANK1 c.2296-2A>G Pathogenic/Likely pathogenic ★★ same condition
ANK1 c.2389-2A>G 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-arg1255cys (accessed [today's date]).

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