Is ANKLE1 p.Pro349His (c.1046C>A) pathogenic?

ANKLE1 p.Pro349His (c.1046C>A) is classified Uncertain significance in ANKLE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely benign (0.1093); Very rare (popmax 0.00167%, amr).

How common is ANKLE1 p.Pro349His (c.1046C>A) in the general population?

ANKLE1 p.Pro349His (c.1046C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ANKLE1 p.Pro349His (c.1046C>A)?

AlphaMissense predicts likely benign (score 0.1093) — an in-silico prediction, not a clinical call.

ANKLE1 p.Pro349His

c.1046C>A · VCV4053262

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1093 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1093	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -0.64
Regional constraint	o/e 0.94	unconstrained · MANE · 4,628 bp · p 0.11 · regional, not allelic
Overall
CADD	14.05	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 0.00167% Admixed American · 1/60,028 alleles

Overall 0.000137% 2/1,461,064 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,028
European (non-Finnish)	8.48e-05%	1,179,908

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: ANKLE1
Protein: p.Pro349His
Coding: c.1046C>A
MANE Select: NM_152363
Type: single nucleotide variant
Location: chr19:17283810 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.14

Full ANKLE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKLE1 c.461-109C>A Benign ★★ same type
ANKLE1 c.*132G>T Benign ★★ same type
ANKLE1 p.Leu524Val Benign ★★ same type
ANKLE1 p.Pro160Ser Benign ★★ same type
ANKLE1 p.Val447Met Benign ★★ same type
ANKLE1 p.Ala103Val Uncertain significance ★ ⚠ same type
ANKLE1 p.Ala143Thr Uncertain significance ★ ⚠ same type
ANKLE1 p.Ala207Val Uncertain significance ★ ⚠ same type

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/ankle1-p-pro349his (accessed [today's date]).

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