Is PGAP3 p.Phe112Ser (c.335T>C) pathogenic?

PGAP3 p.Phe112Ser (c.335T>C) is classified Uncertain significance in PGAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: ambiguous (0.45); Ultra-rare (popmax 0.0214%, afr); Associated with Inborn genetic diseases.

What condition is associated with PGAP3 p.Phe112Ser (c.335T>C)?

PGAP3 p.Phe112Ser (c.335T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PGAP3 p.Phe112Ser (c.335T>C) in the general population?

PGAP3 p.Phe112Ser (c.335T>C) is ultra-rare (popmax 0.0214%, afr) (gnomAD).

What do computational predictors say about PGAP3 p.Phe112Ser (c.335T>C)?

AlphaMissense predicts ambiguous (score 0.45) — an in-silico prediction, not a clinical call.

PGAP3 p.Phe112Ser

c.335T>C · rs772138584 · VCV2335657

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.45 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.45	ambiguous
REVEL	0.344	indeterminate
SaProt	LLR -8.47	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.63 · regional, not allelic
Overall
CADD	27.7	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 0.0214% African / African-American · 16/74,932 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.000992% 16/1,613,680 alleles · ultra-rare exomes 9/1,461,432 · genomes 7/152,248 · 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: PGAP3
Protein: p.Phe112Ser
Coding: c.335T>C
MANE Select: NM_033419
dbSNP: rs772138584
Type: single nucleotide variant
Location: chr17:39684694 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.17

Full PGAP3 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

PGAP3 p.Glu37Ter Pathogenic ★★ same condition
PGAP3 p.Arg126Cys Uncertain significance ★★ ⚠ same condition
PGAP3 p.Gly84Asp Uncertain significance ★★ ⚠ same condition
PGAP3 p.Thr161Ile Uncertain significance ★★ same condition
PGAP3 p.Val145Ala Uncertain significance ★★ same condition
PGAP3 p.Val211Asp Uncertain significance ★★ ⚠ same condition
PGAP3 p.Val253Met Uncertain significance ★★ ⚠ same condition
PGAP3 p.Val280Ala 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/pgap3-p-phe112ser (accessed [today's date]).

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