Is PHEX p.Val231Met (c.691G>A) pathogenic?

PHEX p.Val231Met (c.691G>A) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.1503); Ultra-rare (popmax 0.082%, afr); Associated with Inborn genetic diseases.

What condition is associated with PHEX p.Val231Met (c.691G>A)?

PHEX p.Val231Met (c.691G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PHEX p.Val231Met (c.691G>A) in the general population?

PHEX p.Val231Met (c.691G>A) is ultra-rare (popmax 0.082%, afr) (gnomAD).

What do computational predictors say about PHEX p.Val231Met (c.691G>A)?

AlphaMissense predicts likely benign (score 0.1503) — an in-silico prediction, not a clinical call.

PHEX p.Val231Met

c.691G>A · rs376291775 · VCV2427901

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1503 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.082%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1503	likely benign
REVEL	0.429	indeterminate
SaProt	LLR -4.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	25.2	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 0.082% African / African-American · 47/57,283 alleles

Filtering AF 0.0634% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0568%

Overall 0.0107% 129/1,207,135 alleles · ultra-rare exomes 95/1,094,867 · genomes 34/112,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.082%	1,219
Middle Eastern	0.0692%	1,445
Admixed American	0.0218%	4,581
Remaining individualsnot grpmax-eligible	0.021%	4,751
South Asian	0.0123%	8,108
East Asian	0.0118%	8,440
European (non-Finnish)	0.00538%	18,592

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: PHEX
Protein: p.Val231Met
Coding: c.691G>A
MANE Select: NM_000444
dbSNP: rs376291775
Type: single nucleotide variant
Location: chrX:22090456 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 231: the peptidase m13 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHEX p.Ala524Val Uncertain significance ★★ ⚠ same condition
PHEX p.Arg166His Uncertain significance ★★ ⚠ same condition
PHEX p.Arg443His Uncertain significance ★★ ⚠ same condition
PHEX p.Arg651Trp Uncertain significance ★★ ⚠ same condition
PHEX p.Arg697Lys Uncertain significance ★★ same condition
PHEX p.Asn680Lys Uncertain significance ★★ ⚠ same condition
PHEX p.Asn718Ser Uncertain significance ★★ ⚠ same condition
PHEX p.Asp501Tyr Uncertain significance ★★ ⚠ same condition

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/phex-p-val231met (accessed [today's date]).

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