Is UACA p.Pro425Leu (c.1274C>T) pathogenic?

UACA p.Pro425Leu (c.1274C>T) is classified Uncertain significance in UACA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). AlphaMissense: likely pathogenic (0.6876); Ultra-rare (popmax 0.0165%, sas).

How common is UACA p.Pro425Leu (c.1274C>T) in the general population?

UACA p.Pro425Leu (c.1274C>T) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

What do computational predictors say about UACA p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts likely pathogenic (score 0.6876) — an in-silico prediction, not a clinical call.

UACA p.Pro425Leu

c.1274C>T · rs746136094 · VCV2275602

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6876 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6876	likely pathogenic
REVEL	0.377	indeterminate
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense calls this damaging; SaProt 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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 106 kb · p 0.31 · regional, not allelic
Overall
CADD	27.5	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 0.0165% South Asian · 15/90,996 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.000992% 16/1,613,030 alleles · ultra-rare exomes 16/1,461,056 · genomes 0/151,974 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,066
Remaining individualsnot grpmax-eligible	0.0016%	62,440

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.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_018003
dbSNP: rs746136094
Type: single nucleotide variant
Location: chr15:70669410 (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.Pro425Arg Uncertain significance ★ ⚠ same residue
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

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-pro425leu (accessed [today's date]).

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