Is PHEX p.Val343Ile (c.1027G>A) pathogenic?

PHEX p.Val343Ile (c.1027G>A) is classified Benign in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-23). AlphaMissense: likely benign (0.1868); Ultra-rare (popmax 0.0197%, amr).

How common is PHEX p.Val343Ile (c.1027G>A) in the general population?

PHEX p.Val343Ile (c.1027G>A) is ultra-rare (popmax 0.0197%, amr) (gnomAD).

What do computational predictors say about PHEX p.Val343Ile (c.1027G>A)?

AlphaMissense predicts likely benign (score 0.1868) — an in-silico prediction, not a clinical call.

PHEX p.Val343Ile

c.1027G>A · rs768400503 · VCV1058667

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1868 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1868	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -7.91	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 1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	23.9	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 0.0197% Admixed American · 9/45,621 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00768%

Overall 0.00307% 37/1,206,719 alleles · ultra-rare exomes 34/1,095,540 · genomes 3/111,179 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0197%	5,069
Remaining individualsnot grpmax-eligible	0.0105%	9,498
Ashkenazi Jewishnot grpmax-eligible	0.00454%	22,012
European (non-Finnish)	0.00235%	42,513
South Asian	0.00176%	56,706

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.Val343Ile
Coding: c.1027G>A
MANE Select: NM_000444
dbSNP: rs768400503
Type: single nucleotide variant
Location: chrX:22099099 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 343: 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-val343ile (accessed [today's date]).

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