Is LEFTY2 p.Ala20= (c.60G>A) pathogenic?

LEFTY2 p.Ala20= (c.60G>A) is classified Benign/Likely benign in LEFTY2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-23). Rare (popmax 0.622%, afr); Associated with Left-right axis malformations.

What condition is associated with LEFTY2 p.Ala20= (c.60G>A)?

LEFTY2 p.Ala20= (c.60G>A) is associated with Left-right axis malformations (ClinVar).

How common is LEFTY2 p.Ala20= (c.60G>A) in the general population?

LEFTY2 p.Ala20= (c.60G>A) is rare (popmax 0.622%, afr) (gnomAD).

LEFTY2 p.Ala20=

c.60G>A · rs143444872 · VCV1168973

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.622%, 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 -6	GERP -3.5
Overall
CADD	1.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.622% African / African-American · 465/74,714 alleles

Filtering AF 0.576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.557%

Overall 0.0355% 567/1,598,548 alleles · rare exomes 306/1,446,338 · genomes 261/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.622%	161
Middle Eastern	0.077%	1,298
Remaining individualsnot grpmax-eligible	0.0455%	2,200
Admixed American	0.0425%	2,355
European (non-Finnish)	0.0035%	28,596
South Asian	0.00333%	30,029
Finnishnot grpmax-eligible	0.00164%	60,988

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.Ala20=
Coding: c.60G>A
MANE Select: NM_003240
dbSNP: rs143444872
Type: single nucleotide variant
Location: chr1:225941081 (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.Ala20Val 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-ala20 (accessed [today's date]).

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