Is ANKLE2 p.Pro377Ala (c.1129C>G) pathogenic?

ANKLE2 p.Pro377Ala (c.1129C>G) is classified Uncertain significance in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1311); Very rare (popmax 0.0017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ANKLE2 p.Pro377Ala (c.1129C>G)?

ANKLE2 p.Pro377Ala (c.1129C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ANKLE2 p.Pro377Ala (c.1129C>G) in the general population?

ANKLE2 p.Pro377Ala (c.1129C>G) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about ANKLE2 p.Pro377Ala (c.1129C>G)?

AlphaMissense predicts likely benign (score 0.1311) — an in-silico prediction, not a clinical call.

ANKLE2 p.Pro377Ala

c.1129C>G · VCV4099542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1311	likely benign
REVEL	0.363	indeterminate
SaProt	LLR -7.96	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 4.5	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	22.4	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 0.0017% European (non-Finnish) · 20/1,176,864 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000902%

Overall 0.00137% 22/1,600,724 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,998
European (non-Finnish)grpmax	0.0017%	58,843
Remaining individualsnot grpmax-eligible	0.00161%	61,966

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ANKLE2
Protein: p.Pro377Ala
Coding: c.1129C>G
MANE Select: NM_015114
Type: single nucleotide variant
Location: chr12:132747933 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 377: a UniProt-annotated variant site (in mcph16; uncertain significance)

Full ANKLE2 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

Similar variants

ANKLE2 p.Pro377Leu Uncertain significance ★★ ⚠ same residue
ANKLE2 p.Arg99Ser Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Asn633His Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Asn660Ile Uncertain significance ★★ ⚠ same condition
ANKLE2 p.His893Tyr Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Lys473Arg Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Phe549Val Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Pro37Arg 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/ankle2-p-pro377ala (accessed [today's date]).

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