Is EMC1 p.Arg754= (c.2262C>T) pathogenic?

EMC1 p.Arg754= (c.2262C>T) is classified Conflicting classifications of pathogenicity in EMC1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-10). Ultra-rare (popmax 0.033%, mid).

How common is EMC1 p.Arg754= (c.2262C>T) in the general population?

EMC1 p.Arg754= (c.2262C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

EMC1 p.Arg754=

c.2262C>T · rs145741156 · VCV1524623

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.215	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -2.6, phastCons 0.98
Overall
CADD	6.885	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.00347% 56/1,614,156 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0709%	1,410
Middle Easterngrpmax	0.033%	3,030
Admixed American	0.015%	6,669
Remaining individualsnot grpmax-eligible	0.0144%	6,946
African / African-American	0.00267%	37,519
South Asian	0.0011%	91,086
European (non-Finnish)	0.00102%	98,335

Ashkenazi Jewish 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.Arg754=
Coding: c.2262C>T
MANE Select: NM_015047
dbSNP: rs145741156
Type: single nucleotide variant
Location: chr1:19223510 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB
Residue 754: a turn

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

Similar variants

EMC1 p.Arg754His Uncertain significance ★★ ⚠ same residue
EMC1 p.Arg754Leu Uncertain significance ★★ ⚠ same residue
EMC1 p.Arg754Cys Uncertain significance ★ ⚠ same residue
EMC1 c.287-1G>A Likely pathogenic ★★ same type
EMC1 c.787-1G>A Likely pathogenic ★★ same type
EMC1 p.Arg105Ter Pathogenic/Likely pathogenic ★★ same type
EMC1 p.Arg660Ter Pathogenic/Likely pathogenic ★★ same type
EMC1 p.Arg687Ter Pathogenic/Likely pathogenic ★★ 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/emc1-p-arg754 (accessed [today's date]).

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