Is PHEX p.Ser695Phe (c.2084C>T) pathogenic?

PHEX p.Ser695Phe (c.2084C>T) is classified Uncertain significance in PHEX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.2589); Very rare (popmax 0.00112%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHEX p.Ser695Phe (c.2084C>T)?

PHEX p.Ser695Phe (c.2084C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PHEX p.Ser695Phe (c.2084C>T) in the general population?

PHEX p.Ser695Phe (c.2084C>T) is very rare (popmax 0.00112%, nfe) (gnomAD).

What do computational predictors say about PHEX p.Ser695Phe (c.2084C>T)?

AlphaMissense predicts likely benign (score 0.2589) — an in-silico prediction, not a clinical call.

PHEX p.Ser695Phe

c.2084C>T · rs1020905350 · VCV1956309

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2589 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2589	likely benign
REVEL	0.759	pathogenic-leaning
SaProt	LLR -8.67	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	27.4	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 0.00112% European (non-Finnish) · 10/890,975 alleles

Filtering AF 0.000568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000414%

Overall 0.000829% 10/1,206,650 alleles · very rare exomes 10/1,093,272 · genomes 0/113,378 · joint denominator

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.Ser695Phe
Coding: c.2084C>T
MANE Select: NM_000444
dbSNP: rs1020905350
Type: single nucleotide variant
Location: chrX:22245346 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 695: the peptidase m13 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHEX p.Ser695Cys Uncertain significance ★ ⚠ same residue
PHEX p.Ala524Val Uncertain significance ★★ ⚠ same condition
PHEX p.Arg166His Uncertain significance ★★ ⚠ same condition
PHEX p.Arg443His Uncertain significance ★★ ⚠ same condition
PHEX p.Arg651Trp Uncertain significance ★★ ⚠ same condition
PHEX p.Arg697Lys Uncertain significance ★★ same condition
PHEX p.Asn680Lys Uncertain significance ★★ ⚠ same condition
PHEX p.Asn718Ser Uncertain significance ★★ ⚠ 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-ser695phe (accessed [today's date]).

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