Is EML2 p.Thr286Pro (c.856A>C) pathogenic?

EML2 p.Thr286Pro (c.856A>C) is classified Uncertain significance in EML2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.3623); Ultra-rare (popmax 0.0156%, eas).

How common is EML2 p.Thr286Pro (c.856A>C) in the general population?

EML2 p.Thr286Pro (c.856A>C) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about EML2 p.Thr286Pro (c.856A>C)?

AlphaMissense predicts ambiguous (score 0.3623) — an in-silico prediction, not a clinical call.

EML2 p.Thr286Pro

c.856A>C · rs753869736 · VCV2591288

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3623 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3623	ambiguous
REVEL	0.172	moderately benign-leaning
SaProt	LLR -13.07	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 30 kb · p 0.2 · regional, not allelic
Overall
CADD	26.1	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 0.0156% East Asian · 7/44,864 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00255% 41/1,608,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0481%	2,081
East Asiangrpmax	0.0156%	6,409
African / African-American	0.00267%	37,445
South Asian	0.0022%	45,506

Remaining individuals 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: EML2
Protein: p.Thr286Pro
Coding: c.856A>C
MANE Select: NM_012155
dbSNP: rs753869736
Type: single nucleotide variant
Location: chr19:45621623 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.78 · 1 PDB
Residue 286: 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-thr286pro (accessed [today's date]).

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