Is LANCL2 p.Val280Ala (c.839T>C) pathogenic?

LANCL2 p.Val280Ala (c.839T>C) is classified Uncertain significance in LANCL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1752); Very rare (popmax 0.00696%, nfe).

How common is LANCL2 p.Val280Ala (c.839T>C) in the general population?

LANCL2 p.Val280Ala (c.839T>C) is very rare (popmax 0.00696%, nfe) (gnomAD).

What do computational predictors say about LANCL2 p.Val280Ala (c.839T>C)?

AlphaMissense predicts likely benign (score 0.1752) — an in-silico prediction, not a clinical call.

LANCL2 p.Val280Ala

c.839T>C · rs201948527 · VCV3117784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00696%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1752	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 39 kb · p 3e-05 · regional, not allelic
Overall
CADD	23.0	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 0.00696% European (non-Finnish) · 82/1,178,084 alleles

Filtering AF 0.00572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00526%

Overall 0.00534% 86/1,610,794 alleles · very rare exomes 79/1,458,552 · genomes 7/152,242 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00696%	14,367
Remaining individualsnot grpmax-eligible	0.00321%	31,164
Admixed American	0.00168%	59,688
African / African-American	0.00134%	74,876

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.Val280Ala
Coding: c.839T>C
MANE Select: NM_018697
dbSNP: rs201948527
Type: single nucleotide variant
Location: chr7:55411920 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.37 · 1 PDB

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-val280ala (accessed [today's date]).

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