Is LARGE1 p.Met706Val (c.2116A>G) pathogenic?

LARGE1 p.Met706Val (c.2116A>G) is classified Uncertain significance in LARGE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-24). AlphaMissense: likely pathogenic (0.7867); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LARGE1 p.Met706Val (c.2116A>G)?

LARGE1 p.Met706Val (c.2116A>G) is associated with Inborn genetic diseases (ClinVar).

How common is LARGE1 p.Met706Val (c.2116A>G) in the general population?

LARGE1 p.Met706Val (c.2116A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about LARGE1 p.Met706Val (c.2116A>G)?

AlphaMissense predicts likely pathogenic (score 0.7867) — an in-silico prediction, not a clinical call.

LARGE1 p.Met706Val

c.2116A>G · rs748665662 · VCV2231856

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7867	likely pathogenic
REVEL	0.26	benign-leaning
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 376 kb · p 7.6e-14 · regional, not allelic
Overall
CADD	25.9	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 0.000254% European (non-Finnish) · 3/1,179,982 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,090 alleles · very rare exomes 3/1,461,882 · genomes 0/152,208 · joint denominator

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: LARGE1
Protein: p.Met706Val
Coding: c.2116A>G
MANE Select: NM_133642
dbSNP: rs748665662
Type: single nucleotide variant
Location: chr22:33274582 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.15 · 4 PDB
Residue 706: the 'glucuronyltransferase activity' region

Full LARGE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LARGE1 p.Arg414Gln Uncertain significance ★★ ⚠ same condition
LARGE1 p.Arg60Trp Uncertain significance ★★ ⚠ same condition
LARGE1 p.Asn700Ser Uncertain significance ★★ ⚠ same condition
LARGE1 p.Glu74Asp Uncertain significance ★★ ⚠ same condition
LARGE1 p.Leu83Phe Uncertain significance ★★ ⚠ same condition
LARGE1 p.Met738Thr Uncertain significance ★★ ⚠ same condition
LARGE1 p.Val40Met Uncertain significance ★★ ⚠ same condition
LARGE1 c.492-6C>G Conflicting classifications of pathogenicity ★ 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/large1-p-met706val (accessed [today's date]).

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