Is PUS3 p.Pro375Ser (c.1123C>T) pathogenic?

PUS3 p.Pro375Ser (c.1123C>T) is classified Uncertain significance in PUS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely benign (0.0701); Very rare (popmax 0.00322%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PUS3 p.Pro375Ser (c.1123C>T)?

PUS3 p.Pro375Ser (c.1123C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PUS3 p.Pro375Ser (c.1123C>T) in the general population?

PUS3 p.Pro375Ser (c.1123C>T) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about PUS3 p.Pro375Ser (c.1123C>T)?

AlphaMissense predicts likely benign (score 0.0701) — an in-silico prediction, not a clinical call.

PUS3 p.Pro375Ser

c.1123C>T · VCV4628671

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0701	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.1	GERP -0.96, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 2,496 bp · p 0.059 · regional, not allelic
Overall
CADD	3.581	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 0.00322% European (non-Finnish) · 38/1,179,936 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00254% 41/1,613,858 alleles · very rare exomes 40/1,461,792 · genomes 1/152,066 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,051
African / African-American	0.00267%	37,434
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: PUS3
Protein: p.Pro375Ser
Coding: c.1123C>T
MANE Select: NM_031307
Type: single nucleotide variant
Location: chr11:125894108 (GRCh38)

Full PUS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/pus3-p-pro375ser (accessed [today's date]).

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