Is ASTE1 p.Pro74Leu (c.221C>T) pathogenic?

ASTE1 p.Pro74Leu (c.221C>T) is classified Uncertain significance in ASTE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.491); Absent from gnomAD v4.1.

How common is ASTE1 p.Pro74Leu (c.221C>T) in the general population?

ASTE1 p.Pro74Leu (c.221C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ASTE1 p.Pro74Leu (c.221C>T)?

AlphaMissense predicts ambiguous (score 0.491) — an in-silico prediction, not a clinical call.

ASTE1 p.Pro74Leu

c.221C>T · VCV4157001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.491 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.491	ambiguous
REVEL	0.735	pathogenic-leaning
SaProt	LLR -13.71	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0008 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

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: ASTE1
Protein: p.Pro74Leu
Coding: c.221C>T
MANE Select: NM_014065
Type: single nucleotide variant
Location: chr3:131025086 (GRCh38)
Gene constraint: LOEUF 1.291 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.40

Full ASTE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASTE1 p.Ala202Thr Uncertain significance ★ ⚠ same type
ASTE1 p.Ala219Val Uncertain significance ★ ⚠ same type
ASTE1 p.Ala239Thr Uncertain significance ★ ⚠ same type
ASTE1 p.Ala514Thr Uncertain significance ★ ⚠ same type
ASTE1 p.Ala69Pro Uncertain significance ★ ⚠ same type
ASTE1 p.Arg143Trp Uncertain significance ★ ⚠ same type
ASTE1 p.Arg240His Uncertain significance ★ ⚠ same type
ASTE1 p.Arg255Gln 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/aste1-p-pro74leu (accessed [today's date]).

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