Is PPAT p.Ser63Leu (c.188C>T) pathogenic?

PPAT p.Ser63Leu (c.188C>T) is classified Uncertain significance in PPAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely benign (0.1031); Very rare (popmax 0.00167%, amr).

How common is PPAT p.Ser63Leu (c.188C>T) in the general population?

PPAT p.Ser63Leu (c.188C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PPAT p.Ser63Leu (c.188C>T)?

AlphaMissense predicts likely benign (score 0.1031) — an in-silico prediction, not a clinical call.

PPAT p.Ser63Leu

c.188C>T · rs143863963 · VCV2344023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1031	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -5.14	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 2.3	GERP 0.97, phastCons 0.99
Overall
CADD	17.45	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 0.00167% Admixed American · 1/59,984 alleles

Filtering AF 0.000888% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000726%

Overall 0.00932% 149/1,599,244 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.396%	252
Remaining individualsnot grpmax-eligible	0.0226%	4,432
Admixed Americangrpmax	0.00167%	59,984
European (non-Finnish)	0.00146%	68,613

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: PPAT
Protein: p.Ser63Leu
Coding: c.188C>T
MANE Select: NM_025233 · reported on NM_002703
dbSNP: rs143863963
Type: single nucleotide variant
Location: chr4:56407657 (GRCh38)
Structure: AlphaFold pLDDT 89.51
Residue 63: a UniProt-annotated variant site (in nbia6; reduced protein abundance)

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

Similar variants

COASY p.Glu63= Likely benign ★ same residue
COASY c.1486-3C>G Pathogenic/Likely pathogenic ★★ same type
COASY p.Ala214Val Likely pathogenic ★★ ⚠ same type
COASY p.Arg377Ter Pathogenic/Likely pathogenic ★★ same type
COASY p.Arg499Cys Pathogenic ★★ same type
COASY p.Gln523Ter Pathogenic ★★ same type
COASY p.Ala206Ser Uncertain significance ★★ ⚠ same type
COASY p.Ala311Val 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/ppat-p-ser63leu (accessed [today's date]).

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