Is C6 p.Arg606Gln (c.1817G>A) pathogenic?

C6 p.Arg606Gln (c.1817G>A) is classified Uncertain significance in C6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely benign (0.0652); Very rare (popmax 0.00401%, afr).

How common is C6 p.Arg606Gln (c.1817G>A) in the general population?

C6 p.Arg606Gln (c.1817G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about C6 p.Arg606Gln (c.1817G>A)?

AlphaMissense predicts likely benign (score 0.0652) — an in-silico prediction, not a clinical call.

C6 p.Arg606Gln

c.1817G>A · VCV3612414

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0652	likely benign
SaProt	LLR -7.34	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.7	GERP -3.8
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	0.838	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 0.00401% African / African-American · 3/74,846 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00105% 17/1,613,586 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,949
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,586
East Asian	0.00223%	44,876
Admixed American	0.00167%	59,958
European (non-Finnish)	0.000932%	107,251

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.Arg606Gln
Coding: c.1817G>A
MANE Select: NM_000065
Type: single nucleotide variant
Location: chr5:41159121 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 606: 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

Similar variants

C6 p.Arg606Ter Pathogenic ★★ same residue
C6 p.Arg606= Likely benign ★ same residue
C6 p.Arg596Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Ala21Val Uncertain significance ★★ ⚠ same type
C6 p.Ala396Gly Uncertain significance ★★ ⚠ same type
C6 p.Ala456Thr 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/c6-p-arg606gln (accessed [today's date]).

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