Is EML3 p.Pro61Ser (c.181C>T) pathogenic?

EML3 p.Pro61Ser (c.181C>T) is classified Uncertain significance in EML3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: likely benign (0.0611); Ultra-rare (popmax 0.0248%, nfe).

How common is EML3 p.Pro61Ser (c.181C>T) in the general population?

EML3 p.Pro61Ser (c.181C>T) is ultra-rare (popmax 0.0248%, nfe) (gnomAD).

What do computational predictors say about EML3 p.Pro61Ser (c.181C>T)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

EML3 p.Pro61Ser

c.181C>T · rs199907407 · VCV3088671

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0248%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.25	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 1.8	GERP -0.48, phastCons 0.38
Regional constraint	o/e 1.01	unconstrained · MANE · 2,120 bp · p 0.81 · regional, not allelic
Overall
CADD	12.78	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 0.0248% European (non-Finnish) · 293/1,179,848 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0216%

Overall 0.0206% 333/1,613,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0248%	4,027
Remaining individualsnot grpmax-eligible	0.0192%	5,207
South Asian	0.0176%	5,693
Middle Eastern	0.0165%	6,050
Admixed American	0.01%	9,997
African / African-American	0.004%	25,019
Finnishnot grpmax-eligible	0.00313%	31,953

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.Pro61Ser
Coding: c.181C>T
MANE Select: NM_153265
dbSNP: rs199907407
Type: single nucleotide variant
Location: chr11:62611438 (GRCh38)
Gene constraint: LOEUF 0.63 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.62
Residue 61: 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-pro61ser (accessed [today's date]).

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