Is PHB2 p.Pro73Leu (c.218C>T) pathogenic?

PHB2 p.Pro73Leu (c.218C>T) is classified Uncertain significance in PHB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-06). AlphaMissense: likely pathogenic (0.9726); Absent from gnomAD v4.1.

How common is PHB2 p.Pro73Leu (c.218C>T) in the general population?

PHB2 p.Pro73Leu (c.218C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHB2 p.Pro73Leu (c.218C>T)?

AlphaMissense predicts likely pathogenic (score 0.9726) — an in-silico prediction, not a clinical call.

PHB2 p.Pro73Leu

c.218C>T · rs1946280512 · VCV3211970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9726 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9726	likely pathogenic
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -14.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,544 bp · p 0.00039 · regional, not allelic
Overall
CADD	33.0	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.Pro73Leu
Coding: c.218C>T
MANE Select: NM_001144831
dbSNP: rs1946280512
Type: single nucleotide variant
Location: chr12:6969572 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 85.36 · 8 PDB
Residue 73: a β-strand

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-pro73leu (accessed [today's date]).

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