Is ANKLE2 p.Pro77Leu (c.230C>T) pathogenic?

ANKLE2 p.Pro77Leu (c.230C>T) is classified Conflicting classifications of pathogenicity in ANKLE2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-25). AlphaMissense: likely benign (0.2117); Ultra-rare (popmax 0.041%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ANKLE2 p.Pro77Leu (c.230C>T)?

ANKLE2 p.Pro77Leu (c.230C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ANKLE2 p.Pro77Leu (c.230C>T) in the general population?

ANKLE2 p.Pro77Leu (c.230C>T) is ultra-rare (popmax 0.041%, nfe) (gnomAD).

What do computational predictors say about ANKLE2 p.Pro77Leu (c.230C>T)?

AlphaMissense predicts likely benign (score 0.2117) — an in-silico prediction, not a clinical call.

ANKLE2 p.Pro77Leu

c.230C>T · rs200115455 · VCV1708699

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2117 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.041%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2117	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -7.67	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 8.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 14 kb · p 0.17 · regional, not allelic
Overall
CADD	24.5	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 0.041% European (non-Finnish) · 484/1,179,902 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.0334% 539/1,612,630 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.041%	2,438
South Asian	0.0341%	2,936
Remaining individualsnot grpmax-eligible	0.0304%	3,289
African / African-American	0.00534%	18,742
Finnishnot grpmax-eligible	0.00159%	62,888

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.Pro77Leu
Coding: c.230C>T
MANE Select: NM_015114
dbSNP: rs200115455
Type: single nucleotide variant
Location: chr12:132755085 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 77: the lem domain

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.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.Pro377Leu 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-pro77leu (accessed [today's date]).

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