Is SCO2 p.Pro138Ser (c.412C>T) pathogenic?

SCO2 p.Pro138Ser (c.412C>T) is classified Uncertain significance in SCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-01). AlphaMissense: likely pathogenic (0.8087); Very rare (popmax 0.000169%, nfe).

How common is SCO2 p.Pro138Ser (c.412C>T) in the general population?

SCO2 p.Pro138Ser (c.412C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about SCO2 p.Pro138Ser (c.412C>T)?

AlphaMissense predicts likely pathogenic (score 0.8087) — an in-silico prediction, not a clinical call.

SCO2 p.Pro138Ser

c.412C>T · rs2069208954 · VCV1012707

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.8087	likely pathogenic
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -15.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 797 bp · p 1.7e-05 · regional, not allelic
Overall
CADD	25.3	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 0.000169% European (non-Finnish) · 2/1,180,004 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,612 alleles · very rare exomes 2/1,461,330 · genomes 0/152,282 · joint denominator

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: SCO2
Protein: p.Pro138Ser
Coding: c.412C>T
MANE Select: NM_005138
dbSNP: rs2069208954
Type: single nucleotide variant
Location: chr22:50524000 (GRCh38)

Full SCO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/sco2-p-pro138ser (accessed [today's date]).

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