Is ANKLE1 p.Val446= (c.1338C>T) pathogenic?

ANKLE1 p.Val446= (c.1338C>T) is classified Likely benign in ANKLE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). Ultra-rare (popmax 0.0847%, eas).

How common is ANKLE1 p.Val446= (c.1338C>T) in the general population?

ANKLE1 p.Val446= (c.1338C>T) is ultra-rare (popmax 0.0847%, eas) (gnomAD).

ANKLE1 p.Val446=

c.1338C>T · VCV4099384

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0847%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -3.5
Overall
CADD	0.034	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0847% East Asian · 38/44,868 alleles

Filtering AF 0.0634% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.056%

Overall 0.00744% 120/1,613,748 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0847%	1,181
South Asian	0.0538%	1,859
Remaining individualsnot grpmax-eligible	0.032%	3,124
Admixed American	0.00667%	15,001
African / African-American	0.00533%	18,751
European (non-Finnish)	0.000424%	235,972

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.Val446=
Coding: c.1338C>T
MANE Select: NM_152363
Type: single nucleotide variant
Location: chr19:17284228 (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 p.Val446Ile Uncertain significance ★ ⚠ same residue
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

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-val446 (accessed [today's date]).

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