Is EMC1 p.Arg660Ter (c.1978C>T) pathogenic?

EMC1 p.Arg660Ter (c.1978C>T) is classified Pathogenic/Likely pathogenic in EMC1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-13). Ultra-rare (popmax 0.018%, nfe); Associated with EMC1-related disorder.

What condition is associated with EMC1 p.Arg660Ter (c.1978C>T)?

EMC1 p.Arg660Ter (c.1978C>T) is associated with EMC1-related disorder, cerebellar atrophy, visual impairment, and psychomotor retardation; (ClinVar).

How common is EMC1 p.Arg660Ter (c.1978C>T) in the general population?

EMC1 p.Arg660Ter (c.1978C>T) is ultra-rare (popmax 0.018%, nfe) (gnomAD).

EMC1 p.Arg660Ter

c.1978C>T · rs201271494 · VCV1023218

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, nfe)

Conditions

EMC1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 23
REVEL	0.318	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.7, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.018% European (non-Finnish) · 212/1,180,020 alleles

Filtering AF 0.016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.014% 226/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0192%	5,207
European (non-Finnish)grpmax	0.018%	5,566
African / African-American	0.00267%	37,464

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.Arg660Ter
Coding: c.1978C>T
MANE Select: NM_015047
dbSNP: rs201271494
Type: single nucleotide variant
Location: chr1:19230930 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 660: an α-helix

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

Disease context

EMC1-related disorder

Also linked: cerebellar atrophy, visual impairment, and psychomotor retardation;

Similar variants

EMC1 p.Arg660Gln Uncertain significance ★ ⚠ same residue
EMC1 p.Arg660Gly Uncertain significance ★ ⚠ same residue
EMC1 c.287-1G>A Likely pathogenic ★★ same condition
EMC1 c.787-1G>A Likely pathogenic ★★ same condition
EMC1 p.Arg105Ter Pathogenic/Likely pathogenic ★★ same condition
EMC1 p.Arg687Ter Pathogenic/Likely pathogenic ★★ same condition
EMC1 p.Arg69Ter Pathogenic/Likely pathogenic ★★ same condition
EMC1 p.Leu266Ter Pathogenic/Likely pathogenic ★★ 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/emc1-p-arg660ter (accessed [today's date]).

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