Is LEFTY2 p.Ala116= (c.348C>T) pathogenic?

LEFTY2 p.Ala116= (c.348C>T) is classified Likely benign in LEFTY2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-26). Ultra-rare (popmax 0.0455%, mid); Associated with Left-right axis malformations.

What condition is associated with LEFTY2 p.Ala116= (c.348C>T)?

LEFTY2 p.Ala116= (c.348C>T) is associated with Left-right axis malformations (ClinVar).

How common is LEFTY2 p.Ala116= (c.348C>T) in the general population?

LEFTY2 p.Ala116= (c.348C>T) is ultra-rare (popmax 0.0455%, mid) (gnomAD).

LEFTY2 p.Ala116=

c.348C>T · rs755946624 · VCV259006

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0455%, mid)

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 -9.4	GERP -2.7
Overall
CADD	1.697	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0455% Middle Eastern · 2/4,394 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0282%

Overall 0.00268% 42/1,566,172 alleles · ultra-rare exomes 25/1,413,808 · genomes 17/152,364 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0455%	2,197
African / African-American	0.0442%	2,262
Remaining individualsnot grpmax-eligible	0.00655%	15,259
South Asian	0.00344%	29,097

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.Ala116=
Coding: c.348C>T
MANE Select: NM_003240
dbSNP: rs755946624
Type: single nucleotide variant
Location: chr1:225939905 (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.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
LEFTY2 p.Gln200Glu 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-ala116 (accessed [today's date]).

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