Is USP36 p.Pro630Ser (c.1888C>T) pathogenic?

USP36 p.Pro630Ser (c.1888C>T) is classified Uncertain significance in USP36 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: likely benign (0.0739); Very rare (popmax 0.00667%, amr).

How common is USP36 p.Pro630Ser (c.1888C>T) in the general population?

USP36 p.Pro630Ser (c.1888C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about USP36 p.Pro630Ser (c.1888C>T)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

USP36 p.Pro630Ser

c.1888C>T · VCV3331509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.25	GERP -4.5, phastCons 0.004
Regional constraint	o/e 1.08	unconstrained · MANE · 16 kb · p 0.012 · regional, not allelic
Overall
CADD	0.152	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 0.00667% Admixed American · 4/60,012 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00514% 83/1,614,138 alleles · very rare exomes 79/1,461,886 · genomes 4/152,252 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,003
European (non-Finnish)	0.00593%	16,858
East Asian	0.00445%	22,449
South Asian	0.00439%	22,773
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-American	0.00133%	74,942

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: USP36
Protein: p.Pro630Ser
Coding: c.1888C>T
MANE Select: NM_001385174
Type: single nucleotide variant
Location: chr17:78807156 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.88 · 2 PDB
Residue 630: the 'disordered' region

Full USP36 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP36 p.Arg887Pro Benign ★★ same type
USP36 p.Asn1096= Benign ★★ same type
USP36 p.Asp270= Benign ★★ same type
USP36 p.Gly444Ser Benign ★★ same type
USP36 p.His200Asn Likely benign ★★ ⚠ same type
USP36 p.Phe164= Benign/Likely benign ★★ same type
USP36 p.Pro346= Benign ★★ same type
USP36 p.Pro443= 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/usp36-p-pro630ser (accessed [today's date]).

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