Is PHEX p.Val258Met (c.772G>A) pathogenic?

PHEX p.Val258Met (c.772G>A) is classified Uncertain significance in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2017-06-27). AlphaMissense: likely benign (0.1197); Very rare (popmax 0.00707%, sas).

How common is PHEX p.Val258Met (c.772G>A) in the general population?

PHEX p.Val258Met (c.772G>A) is very rare (popmax 0.00707%, sas) (gnomAD).

What do computational predictors say about PHEX p.Val258Met (c.772G>A)?

AlphaMissense predicts likely benign (score 0.1197) — an in-silico prediction, not a clinical call.

PHEX p.Val258Met

c.772G>A · VCV4949314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00707%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1197	likely benign
REVEL	0.368	indeterminate
SaProt	LLR -8.76	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 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	24.2	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 0.00707% South Asian · 4/56,613 alleles

Filtering AF 0.00235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00141%

Overall 0.000915% 11/1,202,189 alleles · very rare exomes 9/1,090,196 · genomes 2/111,993 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00707%	14,153
African / African-American	0.00175%	57,021
European (non-Finnish)	0.000675%	148,134

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.Val258Met
Coding: c.772G>A
MANE Select: NM_000444
Type: single nucleotide variant
Location: chrX:22094022 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 258: the peptidase m13 domain

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

Similar variants

PHEX c.1079+1G>A Pathogenic ★★ same type
PHEX c.1079+2T>G Pathogenic ★★ same type
PHEX c.1080-1G>A Pathogenic ★★ same type
PHEX c.1080-2A>G Pathogenic ★★ same type
PHEX c.1080-3C>G Pathogenic ★★ same type
PHEX c.1173+1G>A Pathogenic ★★ same type
PHEX c.1173+2T>C Pathogenic ★★ same type
PHEX c.1173+5G>C Likely pathogenic ★★ 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/phex-p-val258met (accessed [today's date]).

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