Is UBASH3A p.Ile463Phe (c.1387A>T) pathogenic?

UBASH3A p.Ile463Phe (c.1387A>T) is classified Uncertain significance in UBASH3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1644); Ultra-rare (popmax 0.035%, amr).

How common is UBASH3A p.Ile463Phe (c.1387A>T) in the general population?

UBASH3A p.Ile463Phe (c.1387A>T) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about UBASH3A p.Ile463Phe (c.1387A>T)?

AlphaMissense predicts likely benign (score 0.1644) — an in-silico prediction, not a clinical call.

UBASH3A p.Ile463Phe

c.1387A>T · rs202199237 · VCV2562833

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1644 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1644	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.77	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 3.4	GERP -3, phastCons 0.57
Regional constraint	o/e 1.00	unconstrained · MANE · 43 kb · p 0.97 · regional, not allelic
Overall
CADD	17.94	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 0.035% Admixed American · 21/60,012 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.0206% 332/1,614,150 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,858
European (non-Finnish)	0.0251%	3,987
Remaining individualsnot grpmax-eligible	0.0176%	5,682
African / African-American	0.00533%	18,767

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: UBASH3A
Protein: p.Ile463Phe
Coding: c.1387A>T
MANE Select: NM_018961
dbSNP: rs202199237
Type: single nucleotide variant
Location: chr21:42434948 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.62 · 2 PDB
Residue 463: the 'phosphatase-like' region; an α-helix

Full UBASH3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIP4 p.Thr555= Benign ★★ same type
UBASH3A c.1393+3A>C Benign ★★ same type
UBASH3A p.Gly601= Benign ★★ same type
UBASH3A p.Ile303= Benign ★★ same type
UBASH3A p.Ile658Val Benign ★★ same type
UBASH3A p.Phe304= Benign ★★ same type
UBASH3A p.Thr144= Benign ★★ same type
UBASH3A p.Thr392= Benign ★★ 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/ubash3a-p-ile463phe (accessed [today's date]).

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