Is EMD p.Arg221Cys (c.661C>T) pathogenic?

EMD p.Arg221Cys (c.661C>T) is classified Uncertain significance in EMD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely benign (0.1808); Very rare (popmax 0.00295%, eas); Associated with Cardiovascular phenotype.

What condition is associated with EMD p.Arg221Cys (c.661C>T)?

EMD p.Arg221Cys (c.661C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EMD p.Arg221Cys (c.661C>T) in the general population?

EMD p.Arg221Cys (c.661C>T) is very rare (popmax 0.00295%, eas) (gnomAD).

What do computational predictors say about EMD p.Arg221Cys (c.661C>T)?

AlphaMissense predicts likely benign (score 0.1808) — an in-silico prediction, not a clinical call.

EMD p.Arg221Cys

c.661C>T · rs1434136213 · VCV3230342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00295%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1808	likely benign
REVEL	0.583	indeterminate
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.39, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	19.41	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00295% East Asian · 1/33,869 alleles

Filtering AF 0.00116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000945%

Overall 0.00173% 19/1,097,916 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00295%	33,869
European (non-Finnish)	0.0019%	52,675
African / African-American	0.00173%	57,958

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.Arg221Cys
Coding: c.661C>T
MANE Select: NM_000117
dbSNP: rs1434136213
Type: single nucleotide variant
Location: chrX:154381093 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB
Residue 221: the 'interaction with f-actin' region

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 p.Arg221His Uncertain significance ★★ ⚠ same residue
EMD p.Arg221Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
EMD p.Arg221= Likely benign ★ same residue
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

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-arg221cys (accessed [today's date]).

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