Is EML3 p.Pro136Ser (c.406C>T) pathogenic?

EML3 p.Pro136Ser (c.406C>T) is classified Uncertain significance in EML3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.0671); Very rare (popmax 0.00996%, sas).

How common is EML3 p.Pro136Ser (c.406C>T) in the general population?

EML3 p.Pro136Ser (c.406C>T) is very rare (popmax 0.00996%, sas) (gnomAD).

What do computational predictors say about EML3 p.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely benign (score 0.0671) — an in-silico prediction, not a clinical call.

EML3 p.Pro136Ser

c.406C>T · rs547084388 · VCV2269468

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00996%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0671	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.15	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 7.2	GERP -0.54, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,120 bp · p 0.81 · regional, not allelic
Overall
CADD	19.04	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 0.00996% South Asian · 9/90,360 alleles

Filtering AF 0.00517% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00125% 20/1,598,430 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00996%	10,040
African / African-American	0.00133%	74,942
European (non-Finnish)	0.000849%	117,789

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: EML3
Protein: p.Pro136Ser
Coding: c.406C>T
MANE Select: NM_153265
dbSNP: rs547084388
Type: single nucleotide variant
Location: chr11:62611133 (GRCh38)
Gene constraint: LOEUF 0.63 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.62
Residue 136: the 'disordered' region

Full EML3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EML3 p.Ala178Ser Uncertain significance ★ ⚠ same type
EML3 p.Ala366Val Uncertain significance ★ ⚠ same type
EML3 p.Ala38Val Uncertain significance ★ ⚠ same type
EML3 p.Ala512Ser Uncertain significance ★ ⚠ same type
EML3 p.Ala875Thr Uncertain significance ★ ⚠ same type
EML3 p.Arg141Gly Uncertain significance ★ ⚠ same type
EML3 p.Arg165Gln Uncertain significance ★ ⚠ same type
EML3 p.Arg165Trp 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/eml3-p-pro136ser (accessed [today's date]).

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