Is LEFTY2 p.Pro3Thr (c.7C>A) pathogenic?

LEFTY2 p.Pro3Thr (c.7C>A) is classified Uncertain significance in LEFTY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.0717); Absent from gnomAD v4.1.

How common is LEFTY2 p.Pro3Thr (c.7C>A) in the general population?

LEFTY2 p.Pro3Thr (c.7C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LEFTY2 p.Pro3Thr (c.7C>A)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

LEFTY2 p.Pro3Thr

c.7C>A · VCV4046810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -3.2
Regional constraint	o/e 0.81	unconstrained · MANE · 3,696 bp · p 2.2e-05 · regional, not allelic
Overall
CADD	1.293	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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: LEFTY2
Protein: p.Pro3Thr
Coding: c.7C>A
MANE Select: NM_003240
Type: single nucleotide variant
Location: chr1:225941134 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.35 (gnomAD)
Structure: AlphaFold pLDDT 79.01

Full LEFTY2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LEFTY2 p.Arg243Gly Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg265Cys Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg314Gln Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg33Trp Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg67His Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg83Gly Uncertain significance ★★ ⚠ same type
LEFTY2 p.Asp241Glu Uncertain significance ★★ same type
LEFTY2 p.Asp356Asn 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/lefty2-p-pro3thr (accessed [today's date]).

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