Is EML2 p.Arg341Ser (c.1021C>A) pathogenic?

EML2 p.Arg341Ser (c.1021C>A) is classified Uncertain significance in EML2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely pathogenic (0.9957); Very rare (popmax 0.00501%, amr).

How common is EML2 p.Arg341Ser (c.1021C>A) in the general population?

EML2 p.Arg341Ser (c.1021C>A) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about EML2 p.Arg341Ser (c.1021C>A)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

EML2 p.Arg341Ser

c.1021C>A · rs770616741 · VCV3088654

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic · top 4% in EML2
REVEL	0.284	benign-leaning
SaProt	LLR -15.79	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.73, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 30 kb · p 0.2 · regional, not allelic
Overall
CADD	24.6	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 0.00501% Admixed American · 3/59,830 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000248% 4/1,609,778 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,943
Finnishnot grpmax-eligible	0.00157%	63,614

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: EML2
Protein: p.Arg341Ser
Coding: c.1021C>A
MANE Select: NM_012155
dbSNP: rs770616741
Type: single nucleotide variant
Location: chr19:45621308 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.78 · 1 PDB
Residue 341: the 'tandem atypical propeller in emls' region

Full EML2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EML2 p.Arg341His Uncertain significance ★ ⚠ same residue
EML2 p.Ala121Val Uncertain significance ★ ⚠ same type
EML2 p.Ala207Ser Uncertain significance ★ ⚠ same type
EML2 p.Ala288Val Uncertain significance ★ ⚠ same type
EML2 p.Ala302Thr Uncertain significance ★ ⚠ same type
EML2 p.Ala384Val Uncertain significance ★ ⚠ same type
EML2 p.Ala473Pro Uncertain significance ★ ⚠ same type
EML2 p.Ala546Thr 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/eml2-p-arg341ser (accessed [today's date]).

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