Is LEFTY2 p.Ala358= (c.1074G>T) pathogenic?

LEFTY2 p.Ala358= (c.1074G>T) is classified Likely benign in LEFTY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-16). Rare (popmax 0.261%, eas); Associated with Left-right axis malformations.

What condition is associated with LEFTY2 p.Ala358= (c.1074G>T)?

LEFTY2 p.Ala358= (c.1074G>T) is associated with Left-right axis malformations (ClinVar).

How common is LEFTY2 p.Ala358= (c.1074G>T) in the general population?

LEFTY2 p.Ala358= (c.1074G>T) is rare (popmax 0.261%, eas) (gnomAD).

LEFTY2 p.Ala358=

c.1074G>T · rs561486852 · VCV468545

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.261%, eas)

Conditions

Left-right axis malformations

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.7
Overall
CADD	0.111	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.261% East Asian · 117/44,890 alleles

Filtering AF 0.222% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.208%

Overall 0.00768% 124/1,613,982 alleles · rare exomes 109/1,461,646 · genomes 15/152,336 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.261%	384
Remaining individualsnot grpmax-eligible	0.008%	12,499
South Asian	0.0022%	45,534

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: LEFTY2
Protein: p.Ala358=
Coding: c.1074G>T
MANE Select: NM_003240
dbSNP: rs561486852
Type: single nucleotide variant
Location: chr1:225937468 (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

Disease context

Left-right axis malformations — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LEFTY2 p.Ala358Val Conflicting classifications of pathogenicity ★ ⚠ same residue
LEFTY2 p.Arg243Gly Uncertain significance ★★ ⚠ same condition
LEFTY2 p.Arg265Cys Uncertain significance ★★ ⚠ same condition
LEFTY2 p.Arg314Gln Uncertain significance ★★ ⚠ same condition
LEFTY2 p.Arg33Trp Uncertain significance ★★ ⚠ same condition
LEFTY2 p.Arg67His Uncertain significance ★★ ⚠ same condition
LEFTY2 p.Asp241Glu Uncertain significance ★★ same condition
LEFTY2 p.Asp356Asn Uncertain significance ★★ ⚠ same condition

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-ala358 (accessed [today's date]).

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