Is C6 p.Arg77Thr (c.230G>C) pathogenic?

C6 p.Arg77Thr (c.230G>C) is classified Conflicting classifications of pathogenicity in C6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-19). AlphaMissense: likely benign (0.061); Ultra-rare (popmax 0.0179%, eas); Associated with Inborn genetic diseases.

What condition is associated with C6 p.Arg77Thr (c.230G>C)?

C6 p.Arg77Thr (c.230G>C) is associated with Inborn genetic diseases (ClinVar).

How common is C6 p.Arg77Thr (c.230G>C) in the general population?

C6 p.Arg77Thr (c.230G>C) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about C6 p.Arg77Thr (c.230G>C)?

AlphaMissense predicts likely benign (score 0.061) — an in-silico prediction, not a clinical call.

C6 p.Arg77Thr

c.230G>C · rs762327241 · VCV2417470

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.061	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -7.18	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 0.73	GERP -3.1
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	1.732	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 0.0179% East Asian · 8/44,804 alleles

Filtering AF 0.00885% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00642%

Overall 0.000496% 8/1,613,578 alleles · ultra-rare

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.Arg77Thr
Coding: c.230G>C
MANE Select: NM_000065
dbSNP: rs762327241
Type: single nucleotide variant
Location: chr5:41201628 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 77: a disulfide bond; the tsp type-1 1 domain; an α-helix

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.Arg77Ser Conflicting classifications of pathogenicity ★ ⚠ 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-arg77thr (accessed [today's date]).

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