Is UACA p.Val216Ile (c.646G>A) pathogenic?

UACA p.Val216Ile (c.646G>A) is classified Uncertain significance in UACA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely benign (0.146); Very rare (popmax 0.00892%, eas).

How common is UACA p.Val216Ile (c.646G>A) in the general population?

UACA p.Val216Ile (c.646G>A) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about UACA p.Val216Ile (c.646G>A)?

AlphaMissense predicts likely benign (score 0.146) — an in-silico prediction, not a clinical call.

UACA p.Val216Ile

c.646G>A · VCV3464873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.146 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.146	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -10.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 106 kb · p 0.31 · 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 0.00892% East Asian · 4/44,842 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000434% 7/1,613,642 alleles · very rare exomes 7/1,461,314 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,210
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	0.00017%	589,877

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: UACA
Protein: p.Val216Ile
Coding: c.646G>A
MANE Select: NM_018003
Type: single nucleotide variant
Location: chr15:70684403 (GRCh38)
Gene constraint: LOEUF 0.833 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.08

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

Similar variants

UACA p.Gln458His Likely benign ★★ same type
UACA c.1222-1G>A Uncertain significance ★ same type
UACA p.Ala1060Ser Uncertain significance ★ ⚠ same type
UACA p.Ala1248Val Uncertain significance ★ ⚠ same type
UACA p.Ala1391Val Uncertain significance ★ ⚠ same type
UACA p.Ala144Val Uncertain significance ★ same type
UACA p.Ala191Val Uncertain significance ★ ⚠ same type
UACA p.Ala203Gly 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/uaca-p-val216ile (accessed [today's date]).

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