Is PHEX p.Lys511Thr (c.1532A>C) pathogenic?

PHEX p.Lys511Thr (c.1532A>C) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.192); Very rare (popmax 0.00438%, amr).

How common is PHEX p.Lys511Thr (c.1532A>C) in the general population?

PHEX p.Lys511Thr (c.1532A>C) is very rare (popmax 0.00438%, amr) (gnomAD).

What do computational predictors say about PHEX p.Lys511Thr (c.1532A>C)?

AlphaMissense predicts likely benign (score 0.192) — an in-silico prediction, not a clinical call.

PHEX p.Lys511Thr

c.1532A>C · rs778363445 · VCV2173816

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00438%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.192	likely benign
REVEL	0.501	indeterminate
SaProt	LLR -8.34	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.74 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	23.7	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 0.00438% Admixed American · 2/45,631 alleles

Filtering AF 0.000727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000279%

Overall 0.000914% 11/1,204,152 alleles · very rare exomes 9/1,091,587 · genomes 2/112,565 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00438%	22,815
Remaining individualsnot grpmax-eligible	0.00212%	47,253
European (non-Finnish)	0.000898%	111,315

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.Lys511Thr
Coding: c.1532A>C
MANE Select: NM_000444
dbSNP: rs778363445
Type: single nucleotide variant
Location: chrX:22178322 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 511: the peptidase m13 domain

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

Similar variants

PHEX p.Lys511Ter Pathogenic ★ same residue
PHEX p.Lys511Asn 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

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-lys511thr (accessed [today's date]).

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