Is PPTC7 p.Asn280Ser (c.839A>G) pathogenic?

PPTC7 p.Asn280Ser (c.839A>G) is classified Uncertain significance in PPTC7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.1525); Very rare (popmax 0.005%, amr).

How common is PPTC7 p.Asn280Ser (c.839A>G) in the general population?

PPTC7 p.Asn280Ser (c.839A>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about PPTC7 p.Asn280Ser (c.839A>G)?

AlphaMissense predicts likely benign (score 0.1525) — an in-silico prediction, not a clinical call.

PPTC7 p.Asn280Ser

c.839A>G · VCV4571500

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1525	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 46 kb · p 1.6e-20 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.005% Admixed American · 3/60,010 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000867% 14/1,614,050 alleles · very rare exomes 13/1,461,842 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
African / African-American	0.00267%	37,461
European (non-Finnish)	0.000763%	131,114

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: PPTC7
Protein: p.Asn280Ser
Coding: c.839A>G
MANE Select: NM_139283
Type: single nucleotide variant
Location: chr12:110538161 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.84
Residue 280: the ppm-type phosphatase domain

Full PPTC7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPTC7 p.Asp158Asn Likely pathogenic ★ same type
PPTC7 p.Ala154Val Uncertain significance ★ ⚠ same type
PPTC7 p.Ala204Val Uncertain significance ★ ⚠ same type
PPTC7 p.Ala300Thr Uncertain significance ★ ⚠ same type
PPTC7 p.Gly157Arg Uncertain significance ★ ⚠ same type
PPTC7 p.Gly167Asp Uncertain significance ★ ⚠ same type
PPTC7 p.Gly28Ser Uncertain significance ★ ⚠ same type
PPTC7 p.Gly35Val 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/pptc7-p-asn280ser (accessed [today's date]).

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