Is PSMC3IP p.Arg25Pro (c.74G>C) pathogenic?

PSMC3IP p.Arg25Pro (c.74G>C) is classified Conflicting classifications of pathogenicity in PSMC3IP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.9797); Very rare (popmax 0.00517%, nfe); Associated with PSMC3IP-related disorder.

What condition is associated with PSMC3IP p.Arg25Pro (c.74G>C)?

PSMC3IP p.Arg25Pro (c.74G>C) is associated with PSMC3IP-related disorder (ClinVar).

How common is PSMC3IP p.Arg25Pro (c.74G>C) in the general population?

PSMC3IP p.Arg25Pro (c.74G>C) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about PSMC3IP p.Arg25Pro (c.74G>C)?

AlphaMissense predicts likely pathogenic (score 0.9797) — an in-silico prediction, not a clinical call.

PSMC3IP p.Arg25Pro

c.74G>C · VCV3939656

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PSMC3IP-related disorder

Computational evidence

Protein change
AlphaMissense	0.9797	likely pathogenic · top 1% in PSMC3IP
REVEL	0.65	pathogenic-leaning
SaProt	LLR -15.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 4,715 bp · p 0.42 · regional, not allelic
Overall
CADD	34.0	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 0.00517% European (non-Finnish) · 61/1,180,036 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.0039% 63/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,345
Remaining individualsnot grpmax-eligible	0.0032%	31,240

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: PSMC3IP
Protein: p.Arg25Pro
Coding: c.74G>C
MANE Select: NM_016556
Type: single nucleotide variant
Location: chr17:42577522 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.45

Full PSMC3IP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PSMC3IP-related disorder

Similar variants

PSMC3IP p.Cys137= Likely benign same condition
PSMC3IP p.Glu160Lys Uncertain significance ★★ ⚠ same type
PSMC3IP c.136-10C>T Benign ★★ same type
PSMC3IP c.225+79G>A Benign ★★ same type
PSMC3IP c.225+89C>T Likely benign ★★ same type
PSMC3IP c.337+88C>T Benign ★★ same type
PSMC3IP c.338-147T>C Benign ★★ same type
PSMC3IP c.338-158G>A Benign ★★ 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/psmc3ip-p-arg25pro (accessed [today's date]).

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