Is PHB2 p.Ser39Pro (c.115T>C) pathogenic?

PHB2 p.Ser39Pro (c.115T>C) is classified Uncertain significance in PHB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: likely pathogenic (0.9933); Absent from gnomAD v4.1.

How common is PHB2 p.Ser39Pro (c.115T>C) in the general population?

PHB2 p.Ser39Pro (c.115T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHB2 p.Ser39Pro (c.115T>C)?

AlphaMissense predicts likely pathogenic (score 0.9933) — an in-silico prediction, not a clinical call.

PHB2 p.Ser39Pro

c.115T>C · rs1555151894 · VCV2338755

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9933 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9933	likely pathogenic
REVEL	0.405	indeterminate
SaProt	LLR -13.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 268 bp · p 0.9 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PHB2
Protein: p.Ser39Pro
Coding: c.115T>C
MANE Select: NM_001144831
dbSNP: rs1555151894
Type: single nucleotide variant
Location: chr12:6970429 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 85.36 · 8 PDB
Residue 39: the 'necessary for transcriptional repression' region

Full PHB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHB2 p.Ser293= Benign ★★ same type
PHB2 p.Thr274= Benign ★★ same type
PHB2 p.Ala22Val Uncertain significance ★ ⚠ same type
PHB2 p.Ala33Val Uncertain significance ★ ⚠ same type
PHB2 p.Arg123Cys Uncertain significance ★ ⚠ same type
PHB2 p.Arg123His Uncertain significance ★ ⚠ same type
PHB2 p.Arg191Gln Uncertain significance ★ ⚠ same type
PHB2 p.Arg209Gln 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/phb2-p-ser39pro (accessed [today's date]).

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