Is EMC1 p.Arg621His (c.1862G>A) pathogenic?

EMC1 p.Arg621His (c.1862G>A) is classified Uncertain significance in EMC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-07). AlphaMissense: likely benign (0.1); Very rare (popmax 0.00331%, sas); Associated with Inborn genetic diseases.

What condition is associated with EMC1 p.Arg621His (c.1862G>A)?

EMC1 p.Arg621His (c.1862G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EMC1 p.Arg621His (c.1862G>A) in the general population?

EMC1 p.Arg621His (c.1862G>A) is very rare (popmax 0.00331%, sas) (gnomAD).

What do computational predictors say about EMC1 p.Arg621His (c.1862G>A)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

EMC1 p.Arg621His

c.1862G>A · rs368763123 · VCV1025925

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.7	GERP 1.4, phastCons 0.99
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 4e-06 · regional, not allelic
Overall
CADD	22.2	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 0.00331% South Asian · 3/90,720 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.000558% 9/1,611,830 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00331%	30,240
Remaining individualsnot grpmax-eligible	0.00321%	31,191
Admixed American	0.00169%	59,128
Finnishnot grpmax-eligible	0.00156%	64,004
African / African-American	0.00134%	74,682
European (non-Finnish)	8.48e-05%	1,179,508

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.Arg621His
Coding: c.1862G>A
dbSNP: rs368763123
Type: single nucleotide variant
Location: chr1:19231343 (GRCh38)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-arg621his (accessed [today's date]).

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