Is C6 p.Arg596Gln (c.1787G>A) pathogenic?

C6 p.Arg596Gln (c.1787G>A) is classified Likely benign in C6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.068); Ultra-rare (popmax 0.0694%, afr); Associated with Inborn genetic diseases.

What condition is associated with C6 p.Arg596Gln (c.1787G>A)?

C6 p.Arg596Gln (c.1787G>A) is associated with Inborn genetic diseases (ClinVar).

How common is C6 p.Arg596Gln (c.1787G>A) in the general population?

C6 p.Arg596Gln (c.1787G>A) is ultra-rare (popmax 0.0694%, afr) (gnomAD).

What do computational predictors say about C6 p.Arg596Gln (c.1787G>A)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

C6 p.Arg596Gln

c.1787G>A · rs148521858 · VCV1137982

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0694%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.005	strongly benign-leaning
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.5	GERP -3.8
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	0.059	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 0.0694% African / African-American · 52/74,980 alleles

Filtering AF 0.0543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0489%

Overall 0.0183% 296/1,613,660 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.301%	332
African / African-Americangrpmax	0.0694%	1,442
Middle Eastern	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.0167%	5,997
European (non-Finnish)	0.0101%	9,914
Finnishnot grpmax-eligible	0.00156%	64,002
South Asian	0.0011%	91,070

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg596Gln
Coding: c.1787G>A
MANE Select: NM_000065
dbSNP: rs148521858
Type: single nucleotide variant
Location: chr5:41159151 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 596: a β-strand; a disulfide bond; the tsp type-1 3 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.Arg596Ter Pathogenic/Likely pathogenic ★★ same residue
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

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-arg596gln (accessed [today's date]).

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