Is C6 p.Leu540Val (c.1618C>G) pathogenic?

C6 p.Leu540Val (c.1618C>G) is classified Uncertain significance in C6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-17). AlphaMissense: likely benign (0.0831); Rare (popmax 0.14%, eas); Associated with Inborn genetic diseases.

What condition is associated with C6 p.Leu540Val (c.1618C>G)?

C6 p.Leu540Val (c.1618C>G) is associated with Inborn genetic diseases (ClinVar).

How common is C6 p.Leu540Val (c.1618C>G) in the general population?

C6 p.Leu540Val (c.1618C>G) is rare (popmax 0.14%, eas) (gnomAD).

What do computational predictors say about C6 p.Leu540Val (c.1618C>G)?

AlphaMissense predicts likely benign (score 0.0831) — an in-silico prediction, not a clinical call.

C6 p.Leu540Val

c.1618C>G · rs190268323 · VCV1465340

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0831 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.14%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0831	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -4.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -2.3, phastCons 0.003
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	9.649	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 0.14% East Asian · 63/44,876 alleles

Filtering AF 0.113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.00415% 67/1,613,902 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.14%	712
Remaining individualsnot grpmax-eligible	0.0048%	20,831
European (non-Finnish)	8.48e-05%	1,179,834

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: C6
Protein: p.Leu540Val
Coding: c.1618C>G
MANE Select: NM_000065
dbSNP: rs190268323
Type: single nucleotide variant
Location: chr5:41160208 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 540: a β-strand; a disulfide bond; the egf-like domain

Full C6 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

C6 p.Ala396Gly Uncertain significance ★★ ⚠ same condition
C6 p.Ala456Thr Uncertain significance ★★ ⚠ same condition
C6 p.Ala500Ser Uncertain significance ★★ ⚠ same condition
C6 p.Arg108His Uncertain significance ★★ ⚠ same condition
C6 p.Arg145His Uncertain significance ★★ ⚠ same condition
C6 p.Arg150His Uncertain significance ★★ ⚠ same condition
C6 p.Arg182Gln Uncertain significance ★★ ⚠ same condition
C6 p.Arg356Gln Uncertain significance ★★ ⚠ 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/c6-p-leu540val (accessed [today's date]).

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