Is PHEX p.Val169Met (c.505G>A) pathogenic?

PHEX p.Val169Met (c.505G>A) is classified Benign/Likely benign in PHEX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely pathogenic (0.63); Ultra-rare (popmax 0.0284%, amr).

How common is PHEX p.Val169Met (c.505G>A) in the general population?

PHEX p.Val169Met (c.505G>A) is ultra-rare (popmax 0.0284%, amr) (gnomAD).

What do computational predictors say about PHEX p.Val169Met (c.505G>A)?

AlphaMissense predicts likely pathogenic (score 0.63) — an in-silico prediction, not a clinical call.

PHEX p.Val169Met

c.505G>A · rs187824835 · VCV387440

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.63 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0284%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.63	likely pathogenic
REVEL	0.548	indeterminate
SaProt	LLR -10.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	24.7	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 0.0284% Admixed American · 13/45,764 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.00364% 44/1,210,063 alleles · ultra-rare exomes 34/1,097,985 · genomes 10/112,078 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0284%	3,520
Middle Eastern	0.023%	4,355
Remaining individualsnot grpmax-eligible	0.0126%	7,936
South Asian	0.00352%	28,417
European (non-Finnish)	0.00235%	42,624
African / African-American	0.00175%	57,289

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.Val169Met
Coding: c.505G>A
MANE Select: NM_000444
dbSNP: rs187824835
Type: single nucleotide variant
Location: chrX:22077544 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 169: the peptidase m13 domain

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

Similar variants

PHEX p.Val169Leu Uncertain significance ★ 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
PHEX c.1173+2T>C 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-val169met (accessed [today's date]).

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