Is ANKLE2 p.Leu603Phe (c.1807C>T) pathogenic?

ANKLE2 p.Leu603Phe (c.1807C>T) is classified Likely benign in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-12-19). AlphaMissense: likely benign (0.2294); Rare (popmax 0.172%, eas).

How common is ANKLE2 p.Leu603Phe (c.1807C>T) in the general population?

ANKLE2 p.Leu603Phe (c.1807C>T) is rare (popmax 0.172%, eas) (gnomAD).

What do computational predictors say about ANKLE2 p.Leu603Phe (c.1807C>T)?

AlphaMissense predicts likely benign (score 0.2294) — an in-silico prediction, not a clinical call.

ANKLE2 p.Leu603Phe

c.1807C>T · rs201330179 · VCV726993

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2294 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.172%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2294	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -10.58	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	24.7	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 0.172% East Asian · 77/44,876 alleles

Filtering AF 0.141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.129%

Overall 0.012% 194/1,614,112 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.172%	583
Finnishnot grpmax-eligible	0.025%	4,001
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.008%	12,502
South Asian	0.00769%	13,012
European (non-Finnish)	0.00737%	13,564
African / African-American	0.00133%	75,006

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.Leu603Phe
Coding: c.1807C>T
MANE Select: NM_015114
dbSNP: rs201330179
Type: single nucleotide variant
Location: chr12:132734469 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 603: a UniProt-annotated variant site (in mcph16; uncertain significance)

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

Similar variants

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
ANKLE2 p.Pro377Leu 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-leu603phe (accessed [today's date]).

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