Is ME3 p.Pro358Leu (c.1073C>T) pathogenic?

ME3 p.Pro358Leu (c.1073C>T) is classified Uncertain significance in ME3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-08). AlphaMissense: likely benign (0.102); Ultra-rare (popmax 0.015%, amr).

How common is ME3 p.Pro358Leu (c.1073C>T) in the general population?

ME3 p.Pro358Leu (c.1073C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about ME3 p.Pro358Leu (c.1073C>T)?

AlphaMissense predicts likely benign (score 0.102) — an in-silico prediction, not a clinical call.

ME3 p.Pro358Leu

c.1073C>T · rs141023220 · VCV3124764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.102 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.102	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 231 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	24.7	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 0.015% Admixed American · 9/59,974 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00273% 44/1,613,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,664
European (non-Finnish)	0.0028%	35,757
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,054

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: ME3
Protein: p.Pro358Leu
Coding: c.1073C>T
MANE Select: NM_001161586
dbSNP: rs141023220
Type: single nucleotide variant
Location: chr11:86449947 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.20 · 7 PDB

Full ME3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ME3 p.Ala21Thr Uncertain significance ★ ⚠ same type
ME3 p.Ala29Glu Uncertain significance ★ ⚠ same type
ME3 p.Ala420Asp Uncertain significance ★ ⚠ same type
ME3 p.Arg10Trp Uncertain significance ★ ⚠ same type
ME3 p.Arg190Cys Uncertain significance ★ ⚠ same type
ME3 p.Arg24Pro Uncertain significance ★ ⚠ same type
ME3 p.Arg289His Uncertain significance ★ ⚠ same type
ME3 p.Arg321Gln 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/me3-p-pro358leu (accessed [today's date]).

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