Is LEFTY2 p.Val125= (c.375C>T) pathogenic?

LEFTY2 p.Val125= (c.375C>T) is classified Likely benign in LEFTY2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.0597%, amr); Associated with Left-right axis malformations.

What condition is associated with LEFTY2 p.Val125= (c.375C>T)?

LEFTY2 p.Val125= (c.375C>T) is associated with Left-right axis malformations (ClinVar).

How common is LEFTY2 p.Val125= (c.375C>T) in the general population?

LEFTY2 p.Val125= (c.375C>T) is ultra-rare (popmax 0.0597%, amr) (gnomAD).

LEFTY2 p.Val125=

c.375C>T · rs757892012 · VCV259007

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0597%, amr)

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 -0.41	GERP -2.4, phastCons 0.001
Overall
CADD	4.525	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0597% Admixed American · 31/51,904 alleles

Filtering AF 0.0432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0376%

Overall 0.032% 495/1,548,192 alleles · ultra-rare exomes 457/1,395,938 · genomes 38/152,254 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0597%	1,674
European (non-Finnish)	0.0384%	2,605
Middle Eastern	0.0228%	4,382
Finnishnot grpmax-eligible	0.0154%	6,493
Remaining individualsnot grpmax-eligible	0.0149%	6,701
African / African-American	0.00541%	18,493

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.Val125=
Coding: c.375C>T
MANE Select: NM_003240
dbSNP: rs757892012
Type: single nucleotide variant
Location: chr1:225939878 (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-val125 (accessed [today's date]).

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