Is EMC3 p.Asp41His (c.121G>C) pathogenic?

EMC3 p.Asp41His (c.121G>C) is classified Uncertain significance in EMC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: ambiguous (0.5477); Very rare (popmax 0.000254%, nfe).

How common is EMC3 p.Asp41His (c.121G>C) in the general population?

EMC3 p.Asp41His (c.121G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about EMC3 p.Asp41His (c.121G>C)?

AlphaMissense predicts ambiguous (score 0.5477) — an in-silico prediction, not a clinical call.

EMC3 p.Asp41His

c.121G>C · rs2085974749 · VCV2263368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5477 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5477	ambiguous
REVEL	0.163	moderately benign-leaning
SaProt	LLR -9.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 0.00032 · regional, not allelic
Overall
CADD	25.8	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 0.000254% European (non-Finnish) · 3/1,180,040 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,074 alleles · very rare

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: EMC3
Protein: p.Asp41His
Coding: c.121G>C
MANE Select: NM_001394674
dbSNP: rs2085974749
Type: single nucleotide variant
Location: chr3:9986541 (GRCh38)
Gene constraint: LOEUF 0.548 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 78.38 · 10 PDB

Full EMC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMC3 p.Asp41Asn Uncertain significance ★ ⚠ same residue
EMC3 c.-242+3401G>A Uncertain significance ★ same type
EMC3 c.-242+3659C>G Uncertain significance ★ same type
EMC3 p.Ala212Thr Uncertain significance ★ ⚠ same type
EMC3 p.Arg180Trp Uncertain significance ★ ⚠ same type
EMC3 p.Arg57Gln Uncertain significance ★ ⚠ same type
EMC3 p.Arg93Trp Uncertain significance ★ ⚠ same type
EMC3 p.Asn175Ser Uncertain significance ★ ⚠ 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/emc3-p-asp41his (accessed [today's date]).

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