Is ELMO3 p.Ser112Leu (c.335C>T) pathogenic?

ELMO3 p.Ser112Leu (c.335C>T) is classified Uncertain significance in ELMO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely benign (0.1035); Ultra-rare (popmax 0.0111%, eas).

How common is ELMO3 p.Ser112Leu (c.335C>T) in the general population?

ELMO3 p.Ser112Leu (c.335C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about ELMO3 p.Ser112Leu (c.335C>T)?

AlphaMissense predicts likely benign (score 0.1035) — an in-silico prediction, not a clinical call.

ELMO3 p.Ser112Leu

c.335C>T · VCV4017576

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1035 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1035	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 0.85
Regional constraint	o/e 0.99	unconstrained · MANE · 4,547 bp · p 0.66 · regional, not allelic
Overall
CADD	21.0	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 0.0111% East Asian · 5/44,880 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00143% 23/1,613,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,929
East Asiangrpmax	0.0111%	8,976
South Asian	0.00768%	13,013
European (non-Finnish)	0.000339%	295,009

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ELMO3
Protein: p.Ser112Leu
Coding: c.335C>T
MANE Select: NM_024712
Type: single nucleotide variant
Location: chr16:67200283 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.04

Full ELMO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ELMO3 p.Val284Ile Likely benign ★★ ⚠ same type
ELMO3 c.1780+1G>A Uncertain significance ★ same type
ELMO3 c.-11C>T Uncertain significance ★ same type
ELMO3 c.-123A>G Uncertain significance ★ same type
ELMO3 c.-14G>T Uncertain significance ★ same type
ELMO3 c.-28G>C Uncertain significance ★ same type
ELMO3 c.-50G>A Uncertain significance ★ same type
ELMO3 c.-77G>A 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/elmo3-p-ser112leu (accessed [today's date]).

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