Is AP2S1 p.Phe95= (c.285C>T) pathogenic?

AP2S1 p.Phe95= (c.285C>T) is classified Conflicting classifications of pathogenicity in AP2S1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-03-03). Rare (popmax 0.132%, mid); Associated with familial hypocalciuric hypercalcemia 3.

What condition is associated with AP2S1 p.Phe95= (c.285C>T)?

AP2S1 p.Phe95= (c.285C>T) is associated with familial hypocalciuric hypercalcemia 3 (ClinVar).

How common is AP2S1 p.Phe95= (c.285C>T) in the general population?

AP2S1 p.Phe95= (c.285C>T) is rare (popmax 0.132%, mid) (gnomAD).

How is Familial hypocalciuric hypercalcemia inherited?

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

AP2S1 p.Phe95=

c.285C>T · rs773768685 · VCV2848182

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Conditions

familial hypocalciuric hypercalcemia 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP -0.49, phastCons 1
Overall
CADD	14.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% Middle Eastern · 8/6,074 alleles

Filtering AF 0.0655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00161% 26/1,613,104 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	759
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,394
Remaining individualsnot grpmax-eligible	0.0016%	62,468
African / African-American	0.00134%	74,868
European (non-Finnish)	0.00102%	98,282

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: AP2S1
Protein: p.Phe95=
Coding: c.285C>T
MANE Select: NM_004069
dbSNP: rs773768685
Type: single nucleotide variant
Location: chr19:46838782 (GRCh38)
Gene constraint: LOEUF 0.478 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.03 · 1 PDB
Residue 95: an α-helix

Full AP2S1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hypocalciuric hypercalcemia 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hypocalciuric hypercalcemia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

AP2S1 p.Arg15Cys Pathogenic ★★ same condition
AP2S1 p.Arg15His Pathogenic/Likely pathogenic ★★ same condition
AP2S1 p.Arg15Leu Pathogenic ★★ same condition
AP2S1 c.153+5C>T Uncertain significance ★★ same condition
AP2S1 p.Thr112Met Uncertain significance ★★ ⚠ same condition
AP2S1 p.Thr129Met Uncertain significance ★★ ⚠ same condition
AP2S1 c.154-32T>G Benign ★★ same condition
AP2S1 p.Ala37= Benign/Likely benign ★★ 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/ap2s1-p-phe95 (accessed [today's date]).

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