Is PSMD2 p.Ala412Ser (c.1234G>T) pathogenic?

PSMD2 p.Ala412Ser (c.1234G>T) is classified Uncertain significance in PSMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely pathogenic (0.6507); Ultra-rare (popmax 0.0136%, nfe).

How common is PSMD2 p.Ala412Ser (c.1234G>T) in the general population?

PSMD2 p.Ala412Ser (c.1234G>T) is ultra-rare (popmax 0.0136%, nfe) (gnomAD).

What do computational predictors say about PSMD2 p.Ala412Ser (c.1234G>T)?

AlphaMissense predicts likely pathogenic (score 0.6507) — an in-silico prediction, not a clinical call.

PSMD2 p.Ala412Ser

c.1234G>T · rs201414592 · VCV2356328

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6507 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6507	likely pathogenic
REVEL	0.466	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 644 bp · p 1.3e-11 · regional, not allelic
Overall
CADD	25.8	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 0.0136% European (non-Finnish) · 161/1,180,046 alleles

Filtering AF 0.0119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.0103% 167/1,614,096 alleles · ultra-rare exomes 159/1,461,884 · genomes 8/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0136%	7,329
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,002
African / African-American	0.00133%	74,928

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: PSMD2
Protein: p.Ala412Ser
Coding: c.1234G>T
MANE Select: NM_002808
dbSNP: rs201414592
Type: single nucleotide variant
Location: chr3:184303660 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.98 · 129 PDB
Residue 412: an α-helix

Full PSMD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSMD2 p.Ala197Ser Uncertain significance ★ ⚠ same type
PSMD2 p.Ala227Thr Uncertain significance ★ ⚠ same type
PSMD2 p.Ala269Thr Uncertain significance ★ ⚠ same type
PSMD2 p.Ala642Thr Uncertain significance ★ ⚠ same type
PSMD2 p.Ala644Thr Uncertain significance ★ ⚠ same type
PSMD2 p.Ala648Gly Uncertain significance ★ ⚠ same type
PSMD2 p.Ala880Thr Uncertain significance ★ ⚠ same type
PSMD2 p.Arg100Cys 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/psmd2-p-ala412ser (accessed [today's date]).

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