Is EML6 p.Ala663Pro (c.1987G>C) pathogenic?

EML6 p.Ala663Pro (c.1987G>C) is classified Uncertain significance in EML6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely benign (0.092); Ultra-rare (popmax 0.0666%, sas).

How common is EML6 p.Ala663Pro (c.1987G>C) in the general population?

EML6 p.Ala663Pro (c.1987G>C) is ultra-rare (popmax 0.0666%, sas) (gnomAD).

What do computational predictors say about EML6 p.Ala663Pro (c.1987G>C)?

AlphaMissense predicts likely benign (score 0.092) — an in-silico prediction, not a clinical call.

EML6 p.Ala663Pro

c.1987G>C · VCV3508388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.092 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0666%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.092	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.7, phastCons 0.96
Regional constraint	o/e 1.20	unconstrained · MANE · 245 kb · p 7.8e-23 · regional, not allelic
Overall
CADD	16.13	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 0.0666% South Asian · 56/84,056 alleles

Filtering AF 0.0527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0476%

Overall 0.00361% 56/1,551,130 alleles · ultra-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: EML6
Protein: p.Ala663Pro
Coding: c.1987G>C
MANE Select: NM_001039753
Type: single nucleotide variant
Location: chr2:54866820 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.42

Full EML6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EML6 p.Arg475Gln Uncertain significance ★★ ⚠ same type
EML6 p.Gly1925Ser Uncertain significance ★★ ⚠ same type
EML6 p.Thr199Ser Uncertain significance ★★ ⚠ same type
EML6 p.Glu1412= Benign ★★ same type
EML6 p.His1237= Benign ★★ same type
EML6 p.His662= Benign ★★ same type
EML6 p.Ile220= Benign ★★ same type
EML6 p.Ala1014Thr 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/eml6-p-ala663pro (accessed [today's date]).

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