Is EMC8 p.Leu29Pro (c.86T>C) pathogenic?

EMC8 p.Leu29Pro (c.86T>C) is classified Uncertain significance in EMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.9971); Very rare (popmax 6.84e-05%).

How common is EMC8 p.Leu29Pro (c.86T>C) in the general population?

EMC8 p.Leu29Pro (c.86T>C) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about EMC8 p.Leu29Pro (c.86T>C)?

AlphaMissense predicts likely pathogenic (score 0.9971) — an in-silico prediction, not a clinical call.

EMC8 p.Leu29Pro

c.86T>C · VCV4248609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9971	likely pathogenic · top 7% in EMC8
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -16.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 20 kb · p 0.73 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 6.84e-05%

Overall 6.84e-05% 1/1,461,154 alleles · very rare

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: EMC8
Protein: p.Leu29Pro
Coding: c.86T>C
MANE Select: NM_006067
Type: single nucleotide variant
Location: chr16:85799210 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 91.60 · 9 PDB
Residue 29: the mpn domain; a β-strand

Full EMC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMC8 p.Ala25Val Uncertain significance ★ ⚠ same type
EMC8 p.Ala32Val Uncertain significance ★ ⚠ same type
EMC8 p.Asp84Val Uncertain significance ★ ⚠ same type
EMC8 p.Glu181Lys Uncertain significance ★ ⚠ same type
EMC8 p.Gly3Trp Uncertain significance ★ ⚠ same type
EMC8 p.His85Arg Uncertain significance ★ ⚠ same type
EMC8 p.Ile125Val Uncertain significance ★ ⚠ same type
EMC8 p.Leu53Phe 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/emc8-p-leu29pro (accessed [today's date]).

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