Is LEFTY2 p.Arg135= (c.405G>A) pathogenic?

LEFTY2 p.Arg135= (c.405G>A) is classified Likely benign in LEFTY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). Very rare (popmax 0.00271%, afr); Associated with Left-right axis malformations.

What condition is associated with LEFTY2 p.Arg135= (c.405G>A)?

LEFTY2 p.Arg135= (c.405G>A) is associated with Left-right axis malformations (ClinVar).

How common is LEFTY2 p.Arg135= (c.405G>A) in the general population?

LEFTY2 p.Arg135= (c.405G>A) is very rare (popmax 0.00271%, afr) (gnomAD).

LEFTY2 p.Arg135=

c.405G>A · rs1260832644 · VCV794674

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00271%, afr)

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 0.15	GERP -0.033, phastCons 0.034
Overall
CADD	10.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00271% African / African-American · 2/73,814 alleles

Filtering AF 0.00045% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000168%

Overall 0.000518% 8/1,544,018 alleles · very rare exomes 5/1,391,778 · genomes 3/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00271%	36,907
European (non-Finnish)	0.000521%	191,820

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.Arg135=
Coding: c.405G>A
MANE Select: NM_003240
dbSNP: rs1260832644
Type: single nucleotide variant
Location: chr1:225939848 (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.Arg135Gln Likely benign ★ 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-arg135 (accessed [today's date]).

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