Is ORMDL3 p.Ser25Pro (c.73T>C) pathogenic?

ORMDL3 p.Ser25Pro (c.73T>C) is classified Uncertain significance in ORMDL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: likely pathogenic (0.9476); Absent from gnomAD v4.1.

How common is ORMDL3 p.Ser25Pro (c.73T>C) in the general population?

ORMDL3 p.Ser25Pro (c.73T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ORMDL3 p.Ser25Pro (c.73T>C)?

AlphaMissense predicts likely pathogenic (score 0.9476) — an in-silico prediction, not a clinical call.

ORMDL3 p.Ser25Pro

c.73T>C · rs2144746568 · VCV2303278

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9476 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9476	likely pathogenic
REVEL	0.377	indeterminate
SaProt	LLR -13.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 1,650 bp · p 0.0012 · regional, not allelic
Overall
CADD	28.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ORMDL3
Protein: p.Ser25Pro
Coding: c.73T>C
MANE Select: NM_139280
dbSNP: rs2144746568
Type: single nucleotide variant
Location: chr17:39924131 (GRCh38)
Gene constraint: LOEUF 0.912 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 94.26 · 13 PDB
Residue 25: an α-helix

Full ORMDL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ORMDL3 p.Ser25Phe Uncertain significance ★ same residue
ORMDL3 p.Arg15Trp Uncertain significance ★ same type
ORMDL3 p.Glu9Lys Uncertain significance ★ ⚠ same type
ORMDL3 p.Gly21Ser Uncertain significance ★ ⚠ same type
ORMDL3 p.His34Tyr Uncertain significance ★ ⚠ same type
ORMDL3 p.Ile147Val Uncertain significance ★ ⚠ same type
ORMDL3 p.Pro41Leu Uncertain significance ★ ⚠ same type
ORMDL3 p.Thr105Ser 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/ormdl3-p-ser25pro (accessed [today's date]).

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