Is PHEX p.Ala257Asp (c.770C>A) pathogenic?

PHEX p.Ala257Asp (c.770C>A) is classified Likely pathogenic in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-13). AlphaMissense: likely pathogenic (0.9966); No allele count reported in gnomAD v4.1 (AN 1,203,029).

How common is PHEX p.Ala257Asp (c.770C>A) in the general population?

PHEX p.Ala257Asp (c.770C>A) is no allele count reported in gnomAD v4.1 (AN 1,203,029) (gnomAD).

What do computational predictors say about PHEX p.Ala257Asp (c.770C>A)?

AlphaMissense predicts likely pathogenic (score 0.9966) — an in-silico prediction, not a clinical call.

PHEX p.Ala257Asp

c.770C>A · rs2519772125 · VCV1937101

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9966 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,203,029)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9966	likely pathogenic ✓ concordant with ClinVar · top 3% in PHEX
REVEL	0.776	moderately pathogenic-leaning
SaProt	LLR -16.75	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 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	26.2	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

No allele count reported in gnomAD v4.1 (AN 1,203,029). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHEX
Protein: p.Ala257Asp
Coding: c.770C>A
MANE Select: NM_000444
dbSNP: rs2519772125
Type: single nucleotide variant
Location: chrX:22094020 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 257: the peptidase m13 domain

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

Similar variants

PHEX p.Ala257= Likely benign ★ same residue
PHEX p.Ala257fs Pathogenic ★ same residue
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

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-ala257asp (accessed [today's date]).

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