Is ANKLE1 p.Arg16Trp (c.46C>T) pathogenic?

ANKLE1 p.Arg16Trp (c.46C>T) is classified Uncertain significance in ANKLE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.1809); Rare (popmax 0.173%, amr).

How common is ANKLE1 p.Arg16Trp (c.46C>T) in the general population?

ANKLE1 p.Arg16Trp (c.46C>T) is rare (popmax 0.173%, amr) (gnomAD).

What do computational predictors say about ANKLE1 p.Arg16Trp (c.46C>T)?

AlphaMissense predicts likely benign (score 0.1809) — an in-silico prediction, not a clinical call.

ANKLE1 p.Arg16Trp

c.46C>T · rs566303446 · VCV2569790

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1809 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.173%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1809	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.7	GERP -1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,628 bp · p 0.11 · regional, not allelic
Overall
CADD	26.8	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 0.173% Admixed American · 88/50,802 alleles

Filtering AF 0.144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.133%

Overall 0.00639% 98/1,533,700 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.173%	577
Remaining individualsnot grpmax-eligible	0.0117%	8,537
African / African-American	0.00274%	36,474
European (non-Finnish)	8.73e-05%	1,145,146

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.Arg16Trp
Coding: c.46C>T
MANE Select: NM_152363
dbSNP: rs566303446
Type: single nucleotide variant
Location: chr19:17281966 (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 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
ANKLE1 p.Ala207Val 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-arg16trp (accessed [today's date]).

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