Is LEFTY2 p.Pro309Arg (c.926C>G) pathogenic?

LEFTY2 p.Pro309Arg (c.926C>G) is classified Uncertain significance in LEFTY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-13). AlphaMissense: likely benign (0.14); Ultra-rare (popmax 0.0111%, eas).

How common is LEFTY2 p.Pro309Arg (c.926C>G) in the general population?

LEFTY2 p.Pro309Arg (c.926C>G) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about LEFTY2 p.Pro309Arg (c.926C>G)?

AlphaMissense predicts likely benign (score 0.14) — an in-silico prediction, not a clinical call.

LEFTY2 p.Pro309Arg

c.926C>G · VCV3290438

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.14 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.14	likely benign
REVEL	0.45	indeterminate
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 3,696 bp · p 2.2e-05 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,884 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000558% 9/1,614,136 alleles · ultra-rare exomes 9/1,461,794 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,977
Remaining individualsnot grpmax-eligible	0.0032%	31,254
South Asian	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,040

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.Pro309Arg
Coding: c.926C>G
MANE Select: NM_003240
Type: single nucleotide variant
Location: chr1:225937616 (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

Similar variants

LEFTY2 p.Arg243Gly Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg265Cys Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg314Gln Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg33Trp Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg67His Uncertain significance ★★ ⚠ same type
LEFTY2 p.Arg83Gly Uncertain significance ★★ ⚠ same type
LEFTY2 p.Asp241Glu Uncertain significance ★★ same type
LEFTY2 p.Asp356Asn Uncertain significance ★★ ⚠ same type

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-pro309arg (accessed [today's date]).

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