Is PPCS p.Met1Leu (c.1A>C) pathogenic?

PPCS p.Met1Leu (c.1A>C) is classified Uncertain significance in PPCS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-12). Very rare (popmax 0.0044%, nfe).

How common is PPCS p.Met1Leu (c.1A>C) in the general population?

PPCS p.Met1Leu (c.1A>C) is very rare (popmax 0.0044%, nfe) (gnomAD).

PPCS p.Met1Leu

c.1A>C · rs765428843 · VCV2183501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0044%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.201	benign-leaning
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.1	GERP 1.1, phastCons 1
Overall
CADD	18.01	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0044% European (non-Finnish) · 49/1,114,448 alleles

Filtering AF 0.00336% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00303%

Overall 0.00346% 51/1,473,898 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0044%	22,744
Remaining individualsnot grpmax-eligible	0.00177%	56,506
African / African-American	0.00143%	69,980

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: PPCS
Protein: p.Met1Leu
Coding: c.1A>C
MANE Select: NM_001395517 · reported on NM_024664
dbSNP: rs765428843
Type: single nucleotide variant
Location: chr1:42456566 (GRCh38)

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

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/ppcs-p-met1leu (accessed [today's date]).

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