Is PSD p.Pro249Ala (c.745C>G) pathogenic?

PSD p.Pro249Ala (c.745C>G) is classified Uncertain significance in PSD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.054); Rare (popmax 0.12%, sas).

How common is PSD p.Pro249Ala (c.745C>G) in the general population?

PSD p.Pro249Ala (c.745C>G) is rare (popmax 0.12%, sas) (gnomAD).

What do computational predictors say about PSD p.Pro249Ala (c.745C>G)?

AlphaMissense predicts likely benign (score 0.054) — an in-silico prediction, not a clinical call.

PSD p.Pro249Ala

c.745C>G · rs753421045 · VCV2588471

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.054 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.12%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.054	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.03	GERP 2, phastCons 0.02
Regional constraint	o/e 0.87	unconstrained · MANE · 4,529 bp · p 0.00029 · regional, not allelic
Overall
CADD	7.931	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 0.12% South Asian · 109/90,810 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0949%

Overall 0.00769% 124/1,613,058 alleles · rare exomes 117/1,460,798 · genomes 7/152,260 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.12%	833
Remaining individualsnot grpmax-eligible	0.0112%	8,923
Finnishnot grpmax-eligible	0.00469%	21,323
European (non-Finnish)	0.000424%	235,906

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: PSD
Protein: p.Pro249Ala
Coding: c.745C>G
MANE Select: NM_002779
dbSNP: rs753421045
Type: single nucleotide variant
Location: chr10:102416029 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 56.76
Residue 249: the 'disordered' region

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

Similar variants

PSD p.Gly336Ser Benign ★★ same type
PSD p.Leu659= Benign ★★ same type
PSD p.Ala1017Pro Uncertain significance ★ ⚠ same type
PSD p.Ala185Pro Uncertain significance ★ ⚠ same type
PSD p.Ala204Val Uncertain significance ★ ⚠ same type
PSD p.Ala260Val Uncertain significance ★ ⚠ same type
PSD p.Ala311Asp Uncertain significance ★ ⚠ same type
PSD p.Ala457Thr 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/psd-p-pro249ala (accessed [today's date]).

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