Is EML5 p.Arg4Gly (c.10C>G) pathogenic?

EML5 p.Arg4Gly (c.10C>G) is classified Uncertain significance in EML5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: ambiguous (0.4216); Ultra-rare (popmax 0.022%, afr).

How common is EML5 p.Arg4Gly (c.10C>G) in the general population?

EML5 p.Arg4Gly (c.10C>G) is ultra-rare (popmax 0.022%, afr) (gnomAD).

What do computational predictors say about EML5 p.Arg4Gly (c.10C>G)?

AlphaMissense predicts ambiguous (score 0.4216) — an in-silico prediction, not a clinical call.

EML5 p.Arg4Gly

c.10C>G · VCV4017849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4216 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4216	ambiguous
REVEL	0.121	moderately benign-leaning
SaProt	LLR -5.94	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 48 kb · p 0.00057 · regional, not allelic
Overall
CADD	25.1	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 0.022% African / African-American · 15/68,136 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.0014% 20/1,423,502 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.022%	4,542
Admixed American	0.00248%	40,326
Remaining individualsnot grpmax-eligible	0.00186%	53,740
European (non-Finnish)	0.000278%	359,792

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: EML5
Protein: p.Arg4Gly
Coding: c.10C>G
MANE Select: NM_183387
Type: single nucleotide variant
Location: chr14:88792494 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18

Full EML5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EML5 p.Ala1787Glu Benign ★★ same type
EML5 p.Thr194Met Benign ★★ same type
EML5 p.Val1361= Benign ★★ same type
EML5 p.Ala1575Thr Uncertain significance ★ ⚠ same type
EML5 p.Ala1606Val Uncertain significance ★ ⚠ same type
EML5 p.Ala1615Val Uncertain significance ★ ⚠ same type
EML5 p.Ala1746Val Uncertain significance ★ ⚠ same type
EML5 p.Ala1787Ser 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/eml5-p-arg4gly (accessed [today's date]).

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