Is ANK1 p.Pro671Ser (c.2011C>T) pathogenic?

ANK1 p.Pro671Ser (c.2011C>T) is classified Uncertain significance in ANK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-30). AlphaMissense: ambiguous (0.3482); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with ANK1 p.Pro671Ser (c.2011C>T)?

ANK1 p.Pro671Ser (c.2011C>T) is associated with Inborn genetic diseases, hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Pro671Ser (c.2011C>T) in the general population?

ANK1 p.Pro671Ser (c.2011C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about ANK1 p.Pro671Ser (c.2011C>T)?

AlphaMissense predicts ambiguous (score 0.3482) — an in-silico prediction, not a clinical call.

ANK1 p.Pro671Ser

c.2011C>T · rs374166500 · VCV2529470

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3482 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3482	ambiguous
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -8.88	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	25.3	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 0.004% African / African-American · 3/74,960 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00297% 48/1,614,020 alleles · very rare exomes 43/1,461,760 · genomes 5/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,987
European (non-Finnish)	0.00381%	26,222

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.Pro671Ser
Coding: c.2011C>T
MANE Select: NM_000037
dbSNP: rs374166500
Type: single nucleotide variant
Location: chr8:41706229 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 671: an α-helix; 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-pro671ser (accessed [today's date]).

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