Is PSMC6 p.Ile331Val (c.991A>G) pathogenic?

PSMC6 p.Ile331Val (c.991A>G) is classified Uncertain significance in PSMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely benign (0.0552); Rare (popmax 0.181%, mid).

How common is PSMC6 p.Ile331Val (c.991A>G) in the general population?

PSMC6 p.Ile331Val (c.991A>G) is rare (popmax 0.181%, mid) (gnomAD).

What do computational predictors say about PSMC6 p.Ile331Val (c.991A>G)?

AlphaMissense predicts likely benign (score 0.0552) — an in-silico prediction, not a clinical call.

PSMC6 p.Ile331Val

c.991A>G · rs150366196 · VCV3220413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0552 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.181%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0552	likely benign
REVEL	0.332	indeterminate
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 6,753 bp · p 2.5e-10 · regional, not allelic
Overall
CADD	20.9	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 0.181% Middle Eastern · 11/6,078 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0784%

Overall 0.00799% 129/1,613,820 alleles · rare exomes 121/1,461,578 · genomes 8/152,242 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.181%	553
Remaining individualsnot grpmax-eligible	0.0208%	4,806
South Asian	0.0187%	5,357
African / African-American	0.00801%	12,489
European (non-Finnish)	0.00695%	14,389

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: PSMC6
Protein: p.Ile331Val
Coding: c.991A>G
MANE Select: NM_002806
dbSNP: rs150366196
Type: single nucleotide variant
Location: chr14:52723976 (GRCh38)
Gene constraint: LOEUF 0.185 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.98 · 82 PDB
Residue 331: an α-helix

Full PSMC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSMC6 c.17T>A Uncertain significance ★ same type
PSMC6 c.-12C>T Uncertain significance ★ same type
PSMC6 c.-20A>G Uncertain significance ★ same type
PSMC6 c.-9C>T Uncertain significance ★ same type
PSMC6 p.Arg356Cys Uncertain significance ★ ⚠ same type
PSMC6 p.Gly5Ser Uncertain significance ★ same type
PSMC6 p.Ile6Leu Uncertain significance ★ same type
PSMC6 p.Pro4Leu 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/psmc6-p-ile331val (accessed [today's date]).

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