Is UACA p.Leu830Pro (c.2489T>C) pathogenic?

UACA p.Leu830Pro (c.2489T>C) is classified Uncertain significance in UACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.8543); Very rare (popmax 0.00017%, nfe).

How common is UACA p.Leu830Pro (c.2489T>C) in the general population?

UACA p.Leu830Pro (c.2489T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about UACA p.Leu830Pro (c.2489T>C)?

AlphaMissense predicts likely pathogenic (score 0.8543) — an in-silico prediction, not a clinical call.

UACA p.Leu830Pro

c.2489T>C · VCV4601063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8543 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8543	likely pathogenic · top 6% in UACA
REVEL	0.628	indeterminate
SaProt	LLR -11.61	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 106 kb · p 0.31 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,179,358 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,610,854 alleles · very rare exomes 2/1,458,678 · genomes 0/152,176 · joint denominator

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.Leu830Pro
Coding: c.2489T>C
MANE Select: NM_018003
Type: single nucleotide variant
Location: chr15:70668195 (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-leu830pro (accessed [today's date]).

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