Is ANKLE2 p.Ser177Leu (c.530C>T) pathogenic?

ANKLE2 p.Ser177Leu (c.530C>T) is classified Conflicting classifications of pathogenicity in ANKLE2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-06-20). AlphaMissense: likely benign (0.0604); Rare (popmax 0.248%, amr).

How common is ANKLE2 p.Ser177Leu (c.530C>T) in the general population?

ANKLE2 p.Ser177Leu (c.530C>T) is rare (popmax 0.248%, amr) (gnomAD).

What do computational predictors say about ANKLE2 p.Ser177Leu (c.530C>T)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

ANKLE2 p.Ser177Leu

c.530C>T · rs185977448 · VCV791426

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.248%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -6.93	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 2.4	GERP -0.58, phastCons 0.054
Regional constraint	o/e 1.07	unconstrained · MANE · 14 kb · p 0.17 · regional, not allelic
Overall
CADD	16.02	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 0.248% Admixed American · 149/60,004 alleles

Filtering AF 0.216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.203%

Overall 0.0759% 1,225/1,614,076 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.248%	403
European (non-Finnish)	0.0867%	1,154
Remaining individualsnot grpmax-eligible	0.0624%	1,603
African / African-American	0.016%	6,249
East Asian	0.00223%	44,876
Finnishnot grpmax-eligible	0.00156%	64,018

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.Ser177Leu
Coding: c.530C>T
MANE Select: NM_015114
dbSNP: rs185977448
Type: single nucleotide variant
Location: chr12:132754785 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14

Full ANKLE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKLE2 p.Ser177Pro Uncertain significance ★ ⚠ same residue
ANKLE2 p.Arg624Ter Pathogenic ★★ same type
ANKLE2 p.Arg99Ser Uncertain significance ★★ ⚠ same type
ANKLE2 p.Asn633His Uncertain significance ★★ ⚠ same type
ANKLE2 p.Asn660Ile Uncertain significance ★★ ⚠ same type
ANKLE2 p.His893Tyr Uncertain significance ★★ ⚠ same type
ANKLE2 p.Lys473Arg Uncertain significance ★★ ⚠ same type
ANKLE2 p.Phe549Val 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/ankle2-p-ser177leu (accessed [today's date]).

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