Is PHPT1 p.Ser94Phe (c.281C>T) pathogenic?

PHPT1 p.Ser94Phe (c.281C>T) is classified Uncertain significance in PHPT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely pathogenic (0.9833); Ultra-rare (popmax 0.0164%, mid).

How common is PHPT1 p.Ser94Phe (c.281C>T) in the general population?

PHPT1 p.Ser94Phe (c.281C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PHPT1 p.Ser94Phe (c.281C>T)?

AlphaMissense predicts likely pathogenic (score 0.9833) — an in-silico prediction, not a clinical call.

PHPT1 p.Ser94Phe

c.281C>T · VCV4136098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9833 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9833	likely pathogenic · top 3% in PHPT1
REVEL	0.595	indeterminate
SaProt	LLR -16.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.3, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 1,413 bp · p 1.3e-05 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00093% 15/1,612,912 alleles · ultra-rare exomes 12/1,460,700 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)	0.0011%	90,761

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: PHPT1
Protein: p.Ser94Phe
Coding: c.281C>T
MANE Select: NM_014172
Type: single nucleotide variant
Location: chr9:136850133 (GRCh38)
Gene constraint: LOEUF 1.546 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.63 · 5 PDB
Residue 94: a binding site

Full PHPT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHPT1 p.Ser94Thr Uncertain significance ★ ⚠ same residue
PHPT1 p.Ser94Tyr Uncertain significance ★ ⚠ same residue
PHPT1 p.Asp123Asn Uncertain significance ★ ⚠ same type
PHPT1 p.Asp58His Uncertain significance ★ ⚠ same type
PHPT1 p.Cys73Trp Uncertain significance ★ ⚠ same type
PHPT1 p.Gln84Arg Uncertain significance ★ ⚠ same type
PHPT1 p.Glu117Asp Uncertain significance ★ ⚠ same type
PHPT1 p.Gly77Arg Uncertain significance ★ ⚠ 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/phpt1-p-ser94phe (accessed [today's date]).

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