Is EMC6 p.Leu84Phe (c.250C>T) pathogenic?

EMC6 p.Leu84Phe (c.250C>T) is classified Uncertain significance in EMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: ambiguous (0.4633); Very rare (popmax 0.00666%, amr).

How common is EMC6 p.Leu84Phe (c.250C>T) in the general population?

EMC6 p.Leu84Phe (c.250C>T) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about EMC6 p.Leu84Phe (c.250C>T)?

AlphaMissense predicts ambiguous (score 0.4633) — an in-silico prediction, not a clinical call.

EMC6 p.Leu84Phe

c.250C>T · VCV4664035

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Computational evidence

Protein change
AlphaMissense	0.4633	ambiguous
REVEL	0.518	indeterminate
SaProt	LLR -9.80	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 329 bp · p 0.007 · regional, not allelic
Overall
CADD	20.4	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 0.00666% Admixed American · 4/60,032 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,614,102 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,008
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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: EMC6
Protein: p.Leu84Phe
Coding: c.250C>T
MANE Select: NM_031298
Type: single nucleotide variant
Location: chr17:3669396 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 10 PDB
Residue 84: an α-helix

Full EMC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMC6 p.Arg20Gln Uncertain significance ★ ⚠ same type
EMC6 p.Arg72Lys Uncertain significance ★ ⚠ same type
EMC6 p.Arg8Leu Uncertain significance ★ ⚠ same type
EMC6 p.Gly42Arg Uncertain significance ★ ⚠ same type
EMC6 p.Gly92Val Uncertain significance ★ ⚠ same type
EMC6 p.Leu49Val Uncertain significance ★ ⚠ same type
EMC6 p.Phe99Leu Uncertain significance ★ ⚠ same type
EMC6 p.Pro83Ala 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/emc6-p-leu84phe (accessed [today's date]).

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