Is PHAX p.Pro91Ser (c.271C>T) pathogenic?

PHAX p.Pro91Ser (c.271C>T) is classified Uncertain significance in PHAX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely benign (0.0842); Rare (popmax 0.261%, afr).

How common is PHAX p.Pro91Ser (c.271C>T) in the general population?

PHAX p.Pro91Ser (c.271C>T) is rare (popmax 0.261%, afr) (gnomAD).

What do computational predictors say about PHAX p.Pro91Ser (c.271C>T)?

AlphaMissense predicts likely benign (score 0.0842) — an in-silico prediction, not a clinical call.

PHAX p.Pro91Ser

c.271C>T · VCV3931391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0842 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.261%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0842	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 24 kb · p 0.36 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.261% African / African-American · 196/75,016 alleles

Filtering AF 0.231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.22%

Overall 0.0153% 247/1,614,118 alleles · rare exomes 122/1,461,884 · genomes 125/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.261%	383
Admixed American	0.0467%	2,143
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0272%	3,677
European (non-Finnish)	0.000339%	295,009

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: PHAX
Protein: p.Pro91Ser
Coding: c.271C>T
MANE Select: NM_032177
Type: single nucleotide variant
Location: chr5:126603744 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.09 · 3 PDB
Residue 91: the 'necessary for interaction with cbp80' region; the 'disordered' region

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

Similar variants

PHAX p.Ala223Val Uncertain significance ★ ⚠ same type
PHAX p.Ala266Thr Uncertain significance ★ ⚠ same type
PHAX p.Ala43Thr Uncertain significance ★ ⚠ same type
PHAX p.Arg248Gln Uncertain significance ★ same type
PHAX p.Arg251Lys Uncertain significance ★ ⚠ same type
PHAX p.Arg281Gln Uncertain significance ★ ⚠ same type
PHAX p.Arg84Gln Uncertain significance ★ ⚠ same type
PHAX p.Asn126Asp 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/phax-p-pro91ser (accessed [today's date]).

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