Is PHEX p.Ser336= (c.1008C>T) pathogenic?

PHEX p.Ser336= (c.1008C>T) is classified Benign/Likely benign in PHEX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-10). Ultra-rare (popmax 0.0353%, sas); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Ser336= (c.1008C>T)?

PHEX p.Ser336= (c.1008C>T) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Ser336= (c.1008C>T) in the general population?

PHEX p.Ser336= (c.1008C>T) is ultra-rare (popmax 0.0353%, sas) (gnomAD).

How is X-linked hypophosphatemia inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

PHEX p.Ser336=

c.1008C>T · rs775973349 · VCV740831

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0353%, sas)

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.2	GERP -2.9
Overall
CADD	0.398	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0353% South Asian · 20/56,670 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.0029% 35/1,205,627 alleles · ultra-rare exomes 33/1,094,372 · genomes 2/111,255 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0353%	2,834
Admixed American	0.00876%	11,412
Ashkenazi Jewishnot grpmax-eligible	0.00455%	21,998
Remaining individualsnot grpmax-eligible	0.00421%	23,746
European (non-Finnish)	0.000897%	111,456

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.Ser336=
Coding: c.1008C>T
MANE Select: NM_000444
dbSNP: rs775973349
Type: single nucleotide variant
Location: chrX:22099080 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 336: the peptidase m13 domain

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

Disease context

X-linked dominant hypophosphatemic rickets — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked hypophosphatemia (Orphanet):

Inheritance: X-linked dominant
Onset: Childhood, Infancy
Prevalence: 1-9 / 100 000 (Norway)

Similar variants

PHEX p.Ser336fs Pathogenic ★ same residue
PHEX c.1079+1G>A Pathogenic ★★ same condition
PHEX c.1079+2T>G Pathogenic ★★ same condition
PHEX c.1080-1G>A Pathogenic ★★ same condition
PHEX c.1080-3C>G Pathogenic ★★ same condition
PHEX c.1173+1G>A Pathogenic ★★ same condition
PHEX c.1173+5G>C Likely pathogenic ★★ same condition
PHEX c.1174-1G>A Pathogenic ★★ same condition

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-ser336 (accessed [today's date]).

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