Is ELMOD2 p.Leu100Pro (c.299T>C) pathogenic?

ELMOD2 p.Leu100Pro (c.299T>C) is classified Uncertain significance in ELMOD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely pathogenic (0.8706); Very rare (popmax 0.000346%, nfe).

How common is ELMOD2 p.Leu100Pro (c.299T>C) in the general population?

ELMOD2 p.Leu100Pro (c.299T>C) is very rare (popmax 0.000346%, nfe) (gnomAD).

What do computational predictors say about ELMOD2 p.Leu100Pro (c.299T>C)?

AlphaMissense predicts likely pathogenic (score 0.8706) — an in-silico prediction, not a clinical call.

ELMOD2 p.Leu100Pro

c.299T>C · VCV3508001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000346%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8706	likely pathogenic
REVEL	0.474	indeterminate
SaProt	LLR -14.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 25 kb · p 0.59 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000346% European (non-Finnish) · 4/1,157,642 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000257% 4/1,554,926 alleles · very rare

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: ELMOD2
Protein: p.Leu100Pro
Coding: c.299T>C
MANE Select: NM_153702
Type: single nucleotide variant
Location: chr4:140537441 (GRCh38)
Gene constraint: LOEUF 0.881 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.39

Full ELMOD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ELMOD2 c.142+43G>T Benign ★★ same type
ELMOD2 c.270-81T>G Benign ★★ same type
ELMOD2 c.-9-294A>G Benign ★★ same type
ELMOD2 c.*9C>T Benign/Likely benign ★★ same type
ELMOD2 p.Lys143Thr Benign/Likely benign ★★ same type
ELMOD2 p.Val39Gly Likely benign ★★ same type
ELMOD2 p.Arg167Ser Uncertain significance ★ ⚠ same type
ELMOD2 p.Asn183Ile 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/elmod2-p-leu100pro (accessed [today's date]).

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