Is EMD p.Leu33Val (c.97C>G) pathogenic?

EMD p.Leu33Val (c.97C>G) is classified Uncertain significance in EMD (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-01). AlphaMissense: ambiguous (0.4149); Very rare (popmax 0.00212%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EMD p.Leu33Val (c.97C>G)?

EMD p.Leu33Val (c.97C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is EMD p.Leu33Val (c.97C>G) in the general population?

EMD p.Leu33Val (c.97C>G) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about EMD p.Leu33Val (c.97C>G)?

AlphaMissense predicts ambiguous (score 0.4149) — an in-silico prediction, not a clinical call.

EMD p.Leu33Val

c.97C>G · rs2522787471 · VCV1768245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4149 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4149	ambiguous
REVEL	0.383	indeterminate
SaProt	LLR -8.17	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	24.5	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 0.00212% European (non-Finnish) · 19/894,794 alleles

Filtering AF 0.00136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00173% 19/1,095,993 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: EMD
Protein: p.Leu33Val
Coding: c.97C>G
MANE Select: NM_000117
dbSNP: rs2522787471
Type: single nucleotide variant
Location: chrX:154379704 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB
Residue 33: the lem domain; an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EMD c.400-3C>T Uncertain significance ★★ same condition
EMD c.449+4C>T Uncertain significance ★★ same condition
EMD p.Arg168Cys Uncertain significance ★★ ⚠ same condition
EMD p.Arg203His Uncertain significance ★★ ⚠ same condition
EMD p.Arg207Gln Uncertain significance ★★ ⚠ same condition
EMD p.Asp72Val Uncertain significance ★★ ⚠ same condition
EMD p.Glu146Lys Uncertain significance ★★ ⚠ same condition
EMD p.Gly24Arg Uncertain significance ★★ ⚠ same condition

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/emd-p-leu33val (accessed [today's date]).

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