Is EML5 p.Ser676Arg (c.2026A>C) pathogenic?

EML5 p.Ser676Arg (c.2026A>C) is classified Uncertain significance in EML5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-14). AlphaMissense: likely pathogenic (0.5695); Ultra-rare (popmax 0.0334%, amr).

How common is EML5 p.Ser676Arg (c.2026A>C) in the general population?

EML5 p.Ser676Arg (c.2026A>C) is ultra-rare (popmax 0.0334%, amr) (gnomAD).

What do computational predictors say about EML5 p.Ser676Arg (c.2026A>C)?

AlphaMissense predicts likely pathogenic (score 0.5695) — an in-silico prediction, not a clinical call.

EML5 p.Ser676Arg

c.2026A>C · rs188732306 · VCV3088707

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5695	likely pathogenic
REVEL	0.054	moderately benign-leaning
SaProt	LLR -5.25	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.83 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 113 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	23.0	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 0.0334% Admixed American · 20/59,944 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00248% 40/1,613,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0334%	2,997
Middle Eastern	0.0165%	6,046
Remaining individualsnot grpmax-eligible	0.0128%	7,804
African / African-American	0.004%	25,007
European (non-Finnish)	0.000678%	147,419

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.Ser676Arg
Coding: c.2026A>C
MANE Select: NM_183387
dbSNP: rs188732306
Type: single nucleotide variant
Location: chr14:88704885 (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-ser676arg (accessed [today's date]).

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