Is ANK1 p.Arg385Cys (c.1153C>T) pathogenic?

ANK1 p.Arg385Cys (c.1153C>T) is classified Conflicting classifications of pathogenicity in ANK1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.7382); Rare (popmax 0.126%, nfe); Associated with immunodeficiency 62.

What condition is associated with ANK1 p.Arg385Cys (c.1153C>T)?

ANK1 p.Arg385Cys (c.1153C>T) is associated with immunodeficiency 62, hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Arg385Cys (c.1153C>T) in the general population?

ANK1 p.Arg385Cys (c.1153C>T) is rare (popmax 0.126%, nfe) (gnomAD).

What do computational predictors say about ANK1 p.Arg385Cys (c.1153C>T)?

AlphaMissense predicts likely pathogenic (score 0.7382) — an in-silico prediction, not a clinical call.

ANK1 p.Arg385Cys

Q: How is Childhood-onset common variable immunodeficiency due to ARHGEF1 deficiency inherited?

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

c.1153C>T · rs142626656 · VCV810949

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7382 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.126%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

immunodeficiency 62

Computational evidence

Protein change
AlphaMissense	0.7382	likely pathogenic
REVEL	0.309	indeterminate
SaProt	LLR -12.74	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 9.9	GERP -0.13, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	27.2	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 0.126% European (non-Finnish) · 1,487/1,180,008 alleles

Filtering AF 0.121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.101% 1,624/1,614,028 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.126%	794
Remaining individualsnot grpmax-eligible	0.0976%	1,025
Admixed American	0.095%	1,053
African / African-American	0.0147%	6,820
Finnishnot grpmax-eligible	0.0125%	7,995

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.Arg385Cys
Coding: c.1153C>T
MANE Select: NM_000037
dbSNP: rs142626656
Type: single nucleotide variant
Location: chr8:41718159 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 385: an α-helix; the '89 kda domain' region

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

Disease context

immunodeficiency 62 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spherocytosis type 1

For Childhood-onset common variable immunodeficiency due to ARHGEF1 deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

ANK1 p.Arg385His 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-arg385cys (accessed [today's date]).

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