Is PPTC7 p.Asp158Asn (c.472G>A) pathogenic?

PPTC7 p.Asp158Asn (c.472G>A) is classified Likely pathogenic in PPTC7 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9912); Very rare (popmax 8.47e-05%, nfe); Associated with Hypomyelinating leukodystrophy.

What condition is associated with PPTC7 p.Asp158Asn (c.472G>A)?

PPTC7 p.Asp158Asn (c.472G>A) is associated with Hypomyelinating leukodystrophy (ClinVar).

How common is PPTC7 p.Asp158Asn (c.472G>A) in the general population?

PPTC7 p.Asp158Asn (c.472G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PPTC7 p.Asp158Asn (c.472G>A)?

AlphaMissense predicts likely pathogenic (score 0.9912) — an in-silico prediction, not a clinical call.

PPTC7 p.Asp158Asn

c.472G>A · VCV4813198

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9912 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hypomyelinating leukodystrophy

Computational evidence

Protein change
AlphaMissense	0.9912	likely pathogenic ✓ concordant with ClinVar
REVEL	0.636	indeterminate
SaProt	LLR -12.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 46 kb · p 1.6e-20 · regional, not allelic
Overall
CADD	32.0	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 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 0.000186% 3/1,614,216 alleles · very rare exomes 3/1,461,856 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	8.47e-05%	1,180,032

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp158Asn
Coding: c.472G>A
MANE Select: NM_139283
Type: single nucleotide variant
Location: chr12:110546010 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.84
Residue 158: the ppm-type phosphatase domain

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

Disease context

Hypomyelinating leukodystrophy

Similar variants

PPTC7 c.*57dup Likely pathogenic ★ same condition
PPTC7 p.Ala154Val Uncertain significance ★ ⚠ same type
PPTC7 p.Ala204Val Uncertain significance ★ ⚠ same type
PPTC7 p.Ala300Thr Uncertain significance ★ ⚠ same type
PPTC7 p.Asn280Ser 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

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-asp158asn (accessed [today's date]).

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