Is LANCL2 p.Ala334Val (c.1001C>T) pathogenic?

LANCL2 p.Ala334Val (c.1001C>T) is classified Uncertain significance in LANCL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely pathogenic (0.7493); Ultra-rare (popmax 0.0165%, mid).

How common is LANCL2 p.Ala334Val (c.1001C>T) in the general population?

LANCL2 p.Ala334Val (c.1001C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about LANCL2 p.Ala334Val (c.1001C>T)?

AlphaMissense predicts likely pathogenic (score 0.7493) — an in-silico prediction, not a clinical call.

LANCL2 p.Ala334Val

c.1001C>T · VCV4096556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7493 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7493	likely pathogenic
REVEL	0.596	indeterminate
SaProt	LLR -11.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 39 kb · p 3e-05 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000806% 13/1,612,546 alleles · ultra-rare exomes 10/1,460,310 · genomes 3/152,236 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Finnishnot grpmax-eligible	0.00312%	32,005
African / African-American	0.00133%	74,940
European (non-Finnish)	0.000763%	130,991

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.Ala334Val
Coding: c.1001C>T
MANE Select: NM_018697
Type: single nucleotide variant
Location: chr7:55412082 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.37 · 1 PDB
Residue 334: 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.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
LANCL2 p.Arg200Trp 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-ala334val (accessed [today's date]).

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