Is EMC1 p.Arg656Trp (c.1966C>T) pathogenic?

EMC1 p.Arg656Trp (c.1966C>T) is classified Uncertain significance in EMC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). AlphaMissense: likely benign (0.205); Very rare (popmax 0.00729%, nfe).

How common is EMC1 p.Arg656Trp (c.1966C>T) in the general population?

EMC1 p.Arg656Trp (c.1966C>T) is very rare (popmax 0.00729%, nfe) (gnomAD).

What do computational predictors say about EMC1 p.Arg656Trp (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.205) — an in-silico prediction, not a clinical call.

EMC1 p.Arg656Trp

c.1966C>T · rs755215386 · VCV1497064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00729%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.205	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -10.34	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 4e-06 · regional, not allelic
Overall
CADD	29.4	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 0.00729% European (non-Finnish) · 86/1,180,046 alleles

Filtering AF 0.00604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.00626% 101/1,614,038 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)grpmax	0.00729%	13,721
Admixed American	0.00667%	14,997
African / African-American	0.00534%	18,733
South Asian	0.0022%	45,541

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EMC1
Protein: p.Arg656Trp
Coding: c.1966C>T
dbSNP: rs755215386
Type: single nucleotide variant
Location: chr1:19230942 (GRCh38)

Full EMC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/emc1-p-arg656trp (accessed [today's date]).

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