Is LEFTY2 p.Pro124Arg (c.371C>G) pathogenic?

LEFTY2 p.Pro124Arg (c.371C>G) is classified Conflicting classifications of pathogenicity in LEFTY2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-24). AlphaMissense: likely benign (0.1463); Ultra-rare (popmax 0.0513%, eas); Associated with Left-right axis malformations.

What condition is associated with LEFTY2 p.Pro124Arg (c.371C>G)?

LEFTY2 p.Pro124Arg (c.371C>G) is associated with Left-right axis malformations (ClinVar).

How common is LEFTY2 p.Pro124Arg (c.371C>G) in the general population?

LEFTY2 p.Pro124Arg (c.371C>G) is ultra-rare (popmax 0.0513%, eas) (gnomAD).

What do computational predictors say about LEFTY2 p.Pro124Arg (c.371C>G)?

AlphaMissense predicts likely benign (score 0.1463) — an in-silico prediction, not a clinical call.

LEFTY2 p.Pro124Arg

c.371C>G · rs777195213 · VCV295973

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1463 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0513%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Left-right axis malformations

Computational evidence

Protein change
AlphaMissense	0.1463	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 3,696 bp · p 2.2e-05 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0513% East Asian · 22/42,862 alleles

Filtering AF 0.0347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00194% 30/1,550,008 alleles · ultra-rare exomes 26/1,397,774 · genomes 4/152,234 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0513%	1,948
South Asian	0.00466%	21,471
Remaining individualsnot grpmax-eligible	0.00166%	60,390
European (non-Finnish)	0.00026%	385,079

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.Pro124Arg
Coding: c.371C>G
MANE Select: NM_003240
dbSNP: rs777195213
Type: single nucleotide variant
Location: chr1:225939882 (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.Pro124= 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-pro124arg (accessed [today's date]).

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