Is PHB1 p.Pro104Ser (c.310C>T) pathogenic?

PHB1 p.Pro104Ser (c.310C>T) is classified Uncertain significance in PHB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-06). AlphaMissense: likely pathogenic (0.7409); Very rare (popmax 0.00136%, nfe).

How common is PHB1 p.Pro104Ser (c.310C>T) in the general population?

PHB1 p.Pro104Ser (c.310C>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about PHB1 p.Pro104Ser (c.310C>T)?

AlphaMissense predicts likely pathogenic (score 0.7409) — an in-silico prediction, not a clinical call.

PHB1 p.Pro104Ser

c.310C>T · rs954452399 · VCV3211969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7409 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7409	likely pathogenic
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -10.02	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 1.8, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 6,724 bp · p 2.2e-17 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,876 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000991% 16/1,613,756 alleles · very rare exomes 15/1,461,544 · genomes 1/152,212 · joint denominator

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.Pro104Ser
Coding: c.310C>T
MANE Select: NM_002634
dbSNP: rs954452399
Type: single nucleotide variant
Location: chr17:49409414 (GRCh38)
Structure: AlphaFold pLDDT 89.36 · 6 PDB

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

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-pro104ser (accessed [today's date]).

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