Is EML2 p.Leu412Pro (c.1235T>C) pathogenic?

EML2 p.Leu412Pro (c.1235T>C) is classified Uncertain significance in EML2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-17). AlphaMissense: likely pathogenic (0.7249); Very rare (popmax 0.000848%, nfe).

How common is EML2 p.Leu412Pro (c.1235T>C) in the general population?

EML2 p.Leu412Pro (c.1235T>C) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about EML2 p.Leu412Pro (c.1235T>C)?

AlphaMissense predicts likely pathogenic (score 0.7249) — an in-silico prediction, not a clinical call.

EML2 p.Leu412Pro

c.1235T>C · rs368360215 · VCV3088655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7249 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7249	likely pathogenic
REVEL	0.208	benign-leaning
SaProt	LLR -13.84	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	GERP -0.39, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 30 kb · p 0.2 · regional, not allelic
Overall
CADD	24.4	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 0.000848% European (non-Finnish) · 10/1,179,154 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,612,508 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: EML2
Protein: p.Leu412Pro
Coding: c.1235T>C
MANE Select: NM_012155
dbSNP: rs368360215
Type: single nucleotide variant
Location: chr19:45619079 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.78 · 1 PDB
Residue 412: 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.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
EML2 p.Ala571Val 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-leu412pro (accessed [today's date]).

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