Is USP39 p.Ser2Phe (c.5C>T) pathogenic?

USP39 p.Ser2Phe (c.5C>T) is classified Uncertain significance in USP39 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.2123); Ultra-rare (popmax 0.022%, mid).

How common is USP39 p.Ser2Phe (c.5C>T) in the general population?

USP39 p.Ser2Phe (c.5C>T) is ultra-rare (popmax 0.022%, mid) (gnomAD).

What do computational predictors say about USP39 p.Ser2Phe (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2123) — an in-silico prediction, not a clinical call.

USP39 p.Ser2Phe

c.5C>T · VCV4828556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2123	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -10.46	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.42	unconstrained · MANE · 3,047 bp · p 3.8e-07 · regional, not allelic
Overall
CADD	24.1	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 0.022% Middle Eastern · 1/4,540 alleles

Filtering AF 0.000582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000459%

Overall 0.00103% 15/1,449,344 alleles · ultra-rare exomes 14/1,297,078 · genomes 1/152,266 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.022%	4,540
Admixed American	0.00267%	37,492
Remaining individualsnot grpmax-eligible	0.00181%	55,350
European (non-Finnish)	0.00109%	91,693

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: USP39
Protein: p.Ser2Phe
Coding: c.5C>T
MANE Select: NM_006590
Type: single nucleotide variant
Location: chr2:85616200 (GRCh38)
Gene constraint: LOEUF 0.744 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.30 · 21 PDB
Residue 2: the 'disordered' region

Full USP39 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP39 p.Ala367Ser Uncertain significance ★ ⚠ same type
USP39 p.Ala40Val Uncertain significance ★ ⚠ same type
USP39 p.Ala41Glu Uncertain significance ★ ⚠ same type
USP39 p.Arg103Cys Uncertain significance ★ ⚠ same type
USP39 p.Arg14Cys Uncertain significance ★ ⚠ same type
USP39 p.Arg14Pro Uncertain significance ★ ⚠ same type
USP39 p.Arg22Gly Uncertain significance ★ ⚠ same type
USP39 p.Arg288Gln 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/usp39-p-ser2phe (accessed [today's date]).

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