Is ASCC2 p.Leu380Pro (c.1139T>C) pathogenic?

ASCC2 p.Leu380Pro (c.1139T>C) is classified Uncertain significance in ASCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely pathogenic (0.9848); Absent from gnomAD v4.1.

How common is ASCC2 p.Leu380Pro (c.1139T>C) in the general population?

ASCC2 p.Leu380Pro (c.1139T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ASCC2 p.Leu380Pro (c.1139T>C)?

AlphaMissense predicts likely pathogenic (score 0.9848) — an in-silico prediction, not a clinical call.

ASCC2 p.Leu380Pro

c.1139T>C · VCV3435304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9848 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9848	likely pathogenic · top 1% in ASCC2
REVEL	0.601	indeterminate
SaProt	LLR -12.54	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 9.3	GERP 2.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 43 kb · p 0.00015 · regional, not allelic
Overall
CADD	26.3	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

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: ASCC2
Protein: p.Leu380Pro
Coding: c.1139T>C
MANE Select: NM_032204
Type: single nucleotide variant
Location: chr22:29806237 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.15 · 2 PDB
Residue 380: an α-helix

Full ASCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASCC2 p.Ala258Val Uncertain significance ★ ⚠ same type
ASCC2 p.Ala26Val Uncertain significance ★ ⚠ same type
ASCC2 p.Ala414Ser Uncertain significance ★ ⚠ same type
ASCC2 p.Ala457Val Uncertain significance ★ ⚠ same type
ASCC2 p.Ala50Thr Uncertain significance ★ ⚠ same type
ASCC2 p.Ala732Asp Uncertain significance ★ ⚠ same type
ASCC2 p.Ala735Val Uncertain significance ★ ⚠ same type
ASCC2 p.Ala738Gly 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/ascc2-p-leu380pro (accessed [today's date]).

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