Is C6 p.Arg504Trp (c.1510C>T) pathogenic?

C6 p.Arg504Trp (c.1510C>T) is classified Uncertain significance in C6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-09). AlphaMissense: ambiguous (0.4751); Ultra-rare (popmax 0.0373%, afr); Associated with Inborn genetic diseases.

What condition is associated with C6 p.Arg504Trp (c.1510C>T)?

C6 p.Arg504Trp (c.1510C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C6 p.Arg504Trp (c.1510C>T) in the general population?

C6 p.Arg504Trp (c.1510C>T) is ultra-rare (popmax 0.0373%, afr) (gnomAD).

What do computational predictors say about C6 p.Arg504Trp (c.1510C>T)?

AlphaMissense predicts ambiguous (score 0.4751) — an in-silico prediction, not a clinical call.

C6 p.Arg504Trp

c.1510C>T · rs752796479 · VCV1367814

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4751 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4751	ambiguous
REVEL	0.741	pathogenic-leaning
SaProt	LLR -15.28	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -2.5, phastCons 0.76
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	24.1	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 0.0373% African / African-American · 28/74,984 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00366% 59/1,613,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0373%	2,678
Admixed American	0.0117%	8,568
East Asian	0.00669%	14,951
Remaining individualsnot grpmax-eligible	0.0064%	15,623
South Asian	0.00549%	18,216
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592
European (non-Finnish)	0.000932%	107,258

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.Arg504Trp
Coding: c.1510C>T
MANE Select: NM_000065
dbSNP: rs752796479
Type: single nucleotide variant
Location: chr5:41160316 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 504: an α-helix; a disulfide bond; the macpf 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.Arg504= Likely benign ★ 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-arg504trp (accessed [today's date]).

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