Is USP36 p.Pro712Ser (c.2134C>T) pathogenic?

USP36 p.Pro712Ser (c.2134C>T) is classified Uncertain significance in USP36 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.0735); Very rare (popmax 0.00134%, afr).

How common is USP36 p.Pro712Ser (c.2134C>T) in the general population?

USP36 p.Pro712Ser (c.2134C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about USP36 p.Pro712Ser (c.2134C>T)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

USP36 p.Pro712Ser

c.2134C>T · VCV3814290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -5.76	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 6.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 16 kb · p 0.012 · regional, not allelic
Overall
CADD	19.8	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 0.00134% African / African-American · 1/74,886 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,746 alleles · very rare exomes 5/1,461,576 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,886
South Asian	0.0011%	91,072
European (non-Finnish)	0.000424%	236,004

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.Pro712Ser
Coding: c.2134C>T
MANE Select: NM_001385174
Type: single nucleotide variant
Location: chr17:78806238 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.88 · 2 PDB
Residue 712: the 'disordered' region

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

Similar variants

USP36 p.Pro712Ala Uncertain significance ★ ⚠ same residue
USP36 p.Pro712Arg Uncertain significance ★ ⚠ same residue
USP36 p.Pro712Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-pro712ser (accessed [today's date]).

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