Is ANK1 p.Pro496Ser (c.1486C>T) pathogenic?

ANK1 p.Pro496Ser (c.1486C>T) is classified Uncertain significance in ANK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-17). AlphaMissense: likely benign (0.2569); Very rare (popmax 0.00797%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ANK1 p.Pro496Ser (c.1486C>T)?

ANK1 p.Pro496Ser (c.1486C>T) is associated with Inborn genetic diseases, hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Pro496Ser (c.1486C>T) in the general population?

ANK1 p.Pro496Ser (c.1486C>T) is very rare (popmax 0.00797%, nfe) (gnomAD).

What do computational predictors say about ANK1 p.Pro496Ser (c.1486C>T)?

AlphaMissense predicts likely benign (score 0.2569) — an in-silico prediction, not a clinical call.

ANK1 p.Pro496Ser

c.1486C>T · rs138685137 · VCV363028

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2569 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00797%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2569	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -12.01	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 8.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	23.3	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 0.00797% European (non-Finnish) · 94/1,180,054 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00595% 96/1,614,096 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00797%	12,554
Remaining individualsnot grpmax-eligible	0.0032%	31,245

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.Pro496Ser
Coding: c.1486C>T
MANE Select: NM_000037
dbSNP: rs138685137
Type: single nucleotide variant
Location: chr8:41715768 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 496: the '89 kda domain' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spherocytosis type 1

Similar variants

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
ANK1 c.2462-2A>G 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-pro496ser (accessed [today's date]).

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