Is PUS1 p.Pro175Ser (c.523C>T) pathogenic?

PUS1 p.Pro175Ser (c.523C>T) is classified Uncertain significance in PUS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-18). AlphaMissense: likely pathogenic (0.5787); Very rare (popmax 0.00684%, afr).

How common is PUS1 p.Pro175Ser (c.523C>T) in the general population?

PUS1 p.Pro175Ser (c.523C>T) is very rare (popmax 0.00684%, afr) (gnomAD).

What do computational predictors say about PUS1 p.Pro175Ser (c.523C>T)?

AlphaMissense predicts likely pathogenic (score 0.5787) — an in-silico prediction, not a clinical call.

PUS1 p.Pro175Ser

c.523C>T · rs777972973 · VCV1698122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00684%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5787	likely pathogenic
REVEL	0.627	indeterminate
SaProt	LLR -9.46	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 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.54 · regional, not allelic
Overall
CADD	27.5	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 0.00684% African / African-American · 5/73,148 alleles

Filtering AF 0.0026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00165%

Overall 0.000321% 5/1,557,448 alleles · very rare exomes 1/1,405,256 · genomes 4/152,192 · joint denominator

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: PUS1
Protein: p.Pro175Ser
Coding: c.523C>T
MANE Select: NM_025215
dbSNP: rs777972973
Type: single nucleotide variant
Location: chr12:131939254 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.80 · 6 PDB

Full PUS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PUS1 p.Pro175= Likely benign ★ same residue
PUS1 p.Gln101Ter Pathogenic/Likely pathogenic ★★ same type
PUS1 p.Gln154Ter Pathogenic ★★ same type
PUS1 p.Lys306Ter Pathogenic/Likely pathogenic ★★ same type
PUS1 p.Trp15Ter Pathogenic/Likely pathogenic ★★ same type
PUS1 p.Trp161Ter Pathogenic/Likely pathogenic ★★ same type
PUS1 p.Ala226Thr Uncertain significance ★★ ⚠ same type
PUS1 p.Ala309Val 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/pus1-p-pro175ser (accessed [today's date]).

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