Is PHB1 p.Val22Met (c.64G>A) pathogenic?

PHB1 p.Val22Met (c.64G>A) is classified Benign in PHB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). AlphaMissense: ambiguous (0.3684); Very rare (popmax 0.00446%, eas); Associated with ovarian cancer.

What condition is associated with PHB1 p.Val22Met (c.64G>A)?

PHB1 p.Val22Met (c.64G>A) is associated with ovarian cancer (ClinVar).

How common is PHB1 p.Val22Met (c.64G>A) in the general population?

PHB1 p.Val22Met (c.64G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PHB1 p.Val22Met (c.64G>A)?

AlphaMissense predicts ambiguous (score 0.3684) — an in-silico prediction, not a clinical call.

PHB1 p.Val22Met

c.64G>A · rs1229985221 · VCV2445301

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3684 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.3684	ambiguous
REVEL	0.095	moderately benign-leaning
SaProt	LLR -9.88	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,544 bp · p 0.063 · regional, not allelic
Overall
CADD	23.5	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 0.00446% East Asian · 2/44,882 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00093% 15/1,612,632 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,441
Admixed American	0.00167%	59,998
Finnishnot grpmax-eligible	0.00158%	63,202
South Asian	0.0011%	91,046
European (non-Finnish)	0.000848%	117,958

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: PHB1
Protein: p.Val22Met
Coding: c.64G>A
MANE Select: NM_002634
dbSNP: rs1229985221
Type: single nucleotide variant
Location: chr17:49413201 (GRCh38)
Structure: AlphaFold pLDDT 89.36 · 6 PDB

Full PHB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHB1 c.511-12C>G Benign ★★ same type
PHB1 p.Leu251= Benign ★★ same type
PHB1 p.Ala244Val Uncertain significance ★ ⚠ same type
PHB1 p.Arg43Gly Uncertain significance ★ same type
PHB1 p.Arg72Gln Uncertain significance ★ ⚠ same type
PHB1 p.Arg93Cys Uncertain significance ★ ⚠ same type
PHB1 p.Asp68Tyr Uncertain significance ★ ⚠ same type
PHB1 p.Gln264Arg 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/phb1-p-val22met (accessed [today's date]).

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