Is LEFTY2 p.Arg66= (c.198G>A) pathogenic?

LEFTY2 p.Arg66= (c.198G>A) is classified Benign in LEFTY2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-06). Rare (popmax 0.627%, sas); Associated with Left-right axis malformations.

What condition is associated with LEFTY2 p.Arg66= (c.198G>A)?

LEFTY2 p.Arg66= (c.198G>A) is associated with Left-right axis malformations (ClinVar).

How common is LEFTY2 p.Arg66= (c.198G>A) in the general population?

LEFTY2 p.Arg66= (c.198G>A) is rare (popmax 0.627%, sas) (gnomAD).

LEFTY2 p.Arg66=

c.198G>A · rs374435067 · VCV536418

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.627%, sas)

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 0.62	GERP -0.51, phastCons 1
Overall
CADD	8.454	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.627% South Asian · 571/91,074 alleles

Filtering AF 0.584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.568%

Overall 0.0377% 609/1,613,714 alleles · rare exomes 581/1,461,386 · genomes 28/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.627%	159
Remaining individualsnot grpmax-eligible	0.0432%	2,314
African / African-American	0.00266%	37,524
European (non-Finnish)	0.000763%	131,095

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.Arg66=
Coding: c.198G>A
MANE Select: NM_003240
dbSNP: rs374435067
Type: single nucleotide variant
Location: chr1:225940943 (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.Arg66Leu Uncertain significance ★ ⚠ 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-arg66 (accessed [today's date]).

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