Is EML6 p.Ala554Val (c.1661C>T) pathogenic?

EML6 p.Ala554Val (c.1661C>T) is classified Uncertain significance in EML6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely pathogenic (0.6337); Very rare (popmax 8.73e-05%, nfe).

How common is EML6 p.Ala554Val (c.1661C>T) in the general population?

EML6 p.Ala554Val (c.1661C>T) is very rare (popmax 8.73e-05%, nfe) (gnomAD).

What do computational predictors say about EML6 p.Ala554Val (c.1661C>T)?

AlphaMissense predicts likely pathogenic (score 0.6337) — an in-silico prediction, not a clinical call.

EML6 p.Ala554Val

c.1661C>T · VCV4664204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.73e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6337	likely pathogenic
REVEL	0.417	indeterminate
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 245 kb · p 7.8e-23 · regional, not allelic
Overall
CADD	26.9	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 8.73e-05% European (non-Finnish) · 1/1,146,016 alleles

Overall 7.16e-05% 1/1,395,780 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: EML6
Protein: p.Ala554Val
Coding: c.1661C>T
MANE Select: NM_001039753
Type: single nucleotide variant
Location: chr2:54859537 (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-ala554val (accessed [today's date]).

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