Is PSME4 p.Leu289Val (c.865C>G) pathogenic?

PSME4 p.Leu289Val (c.865C>G) is classified Uncertain significance in PSME4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.6239); Very rare (popmax 0.000514%, nfe).

How common is PSME4 p.Leu289Val (c.865C>G) in the general population?

PSME4 p.Leu289Val (c.865C>G) is very rare (popmax 0.000514%, nfe) (gnomAD).

What do computational predictors say about PSME4 p.Leu289Val (c.865C>G)?

AlphaMissense predicts likely pathogenic (score 0.6239) — an in-silico prediction, not a clinical call.

PSME4 p.Leu289Val

c.865C>G · VCV4146650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000514%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6239	likely pathogenic
REVEL	0.191	benign-leaning
SaProt	LLR -4.50	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 43 kb · p 0.4 · regional, not allelic
Overall
CADD	25.5	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 0.000514% European (non-Finnish) · 6/1,167,440 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000375% 6/1,599,296 alleles · very rare exomes 3/1,447,210 · genomes 3/152,086 · 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: PSME4
Protein: p.Leu289Val
Coding: c.865C>G
MANE Select: NM_014614
Type: single nucleotide variant
Location: chr2:53934697 (GRCh38)
Gene constraint: LOEUF 0.393 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.29 · 5 PDB

Full PSME4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSME4 p.Ala1137Asp Uncertain significance ★ ⚠ same type
PSME4 p.Ala120Thr Uncertain significance ★ ⚠ same type
PSME4 p.Ala1622Ser Uncertain significance ★ ⚠ same type
PSME4 p.Ala190Thr Uncertain significance ★ ⚠ same type
PSME4 p.Arg1131Cys Uncertain significance ★ ⚠ same type
PSME4 p.Arg1176Ile Uncertain significance ★ ⚠ same type
PSME4 p.Arg1187Trp Uncertain significance ★ ⚠ same type
PSME4 p.Arg121Cys 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/psme4-p-leu289val (accessed [today's date]).

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