Is LANCL2 p.Val227Ala (c.680T>C) pathogenic?

LANCL2 p.Val227Ala (c.680T>C) is classified Uncertain significance in LANCL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-22). AlphaMissense: ambiguous (0.3662); Very rare (popmax 0.00446%, eas).

How common is LANCL2 p.Val227Ala (c.680T>C) in the general population?

LANCL2 p.Val227Ala (c.680T>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about LANCL2 p.Val227Ala (c.680T>C)?

AlphaMissense predicts ambiguous (score 0.3662) — an in-silico prediction, not a clinical call.

LANCL2 p.Val227Ala

c.680T>C · rs771684906 · VCV3117782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
AlphaMissense	0.3662	ambiguous
REVEL	0.501	indeterminate
SaProt	LLR -12.19	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 39 kb · p 3e-05 · regional, not allelic
Overall
CADD	27.3	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 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000186% 3/1,613,754 alleles · very rare exomes 3/1,461,454 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,439
European (non-Finnish)	8.48e-05%	1,179,674

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: LANCL2
Protein: p.Val227Ala
Coding: c.680T>C
MANE Select: NM_018697
dbSNP: rs771684906
Type: single nucleotide variant
Location: chr7:55401175 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.37 · 1 PDB
Residue 227: an α-helix

Full LANCL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LANCL2 p.Ala277Val Uncertain significance ★ ⚠ same type
LANCL2 p.Ala334Val Uncertain significance ★ ⚠ same type
LANCL2 p.Ala35Pro Uncertain significance ★ ⚠ same type
LANCL2 p.Ala37Glu Uncertain significance ★ ⚠ same type
LANCL2 p.Ala424Thr Uncertain significance ★ ⚠ same type
LANCL2 p.Ala44Val Uncertain significance ★ ⚠ same type
LANCL2 p.Arg128Gln Uncertain significance ★ ⚠ same type
LANCL2 p.Arg183Ile 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/lancl2-p-val227ala (accessed [today's date]).

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