Is ANKRD1 p.Pro52Ala (c.154C>G) pathogenic?

ANKRD1 p.Pro52Ala (c.154C>G) is classified Uncertain significance in ANKRD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-17). AlphaMissense: likely benign (0.062); Ultra-rare (popmax 0.03%, amr); Associated with Cardiovascular phenotype.

What condition is associated with ANKRD1 p.Pro52Ala (c.154C>G)?

ANKRD1 p.Pro52Ala (c.154C>G) is associated with Cardiovascular phenotype, cardiomyopathy (ClinVar).

How common is ANKRD1 p.Pro52Ala (c.154C>G) in the general population?

ANKRD1 p.Pro52Ala (c.154C>G) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about ANKRD1 p.Pro52Ala (c.154C>G)?

AlphaMissense predicts likely benign (score 0.062) — an in-silico prediction, not a clinical call.

ANKRD1 p.Pro52Ala

c.154C>G · rs397517248 · VCV263990

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.062	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -1.8, phastCons 0.97
Regional constraint	o/e 0.93	unconstrained · MANE · 8,158 bp · p 0.17 · regional, not allelic
Overall
CADD	3.207	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/59,996 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00483% 78/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,333
South Asian	0.0264%	3,792
Middle Eastern	0.0166%	6,038
Remaining individualsnot grpmax-eligible	0.0032%	31,250
African / African-American	0.00267%	37,519
European (non-Finnish)	0.00254%	39,334
Finnishnot grpmax-eligible	0.00156%	64,020

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: ANKRD1
Protein: p.Pro52Ala
Coding: c.154C>G
MANE Select: NM_014391
dbSNP: rs397517248
Type: single nucleotide variant
Location: chr10:90920222 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.64

Full ANKRD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy

Similar variants

ANKRD1 p.Pro52Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
ANKRD1 p.Pro52Arg Uncertain significance ★ ⚠ same residue
ANKRD1 c.207+1G>T Uncertain significance ★★ same condition
ANKRD1 c.27+1G>T Uncertain significance ★★ same condition
ANKRD1 c.28-3T>C Uncertain significance ★★ same condition
ANKRD1 c.651+4T>A Uncertain significance ★★ same condition
ANKRD1 c.651+6C>T Uncertain significance ★★ same condition
ANKRD1 c.750+2T>C Uncertain significance ★★ 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/ankrd1-p-pro52ala (accessed [today's date]).

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