Is C7 p.Pro681Arg (c.2042C>G) pathogenic?

C7 p.Pro681Arg (c.2042C>G) is classified Uncertain significance in C7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely benign (0.2764); Ultra-rare (popmax 0.0343%, sas).

How common is C7 p.Pro681Arg (c.2042C>G) in the general population?

C7 p.Pro681Arg (c.2042C>G) is ultra-rare (popmax 0.0343%, sas) (gnomAD).

What do computational predictors say about C7 p.Pro681Arg (c.2042C>G)?

AlphaMissense predicts likely benign (score 0.2764) — an in-silico prediction, not a clinical call.

C7 p.Pro681Arg

c.2042C>G · rs560966807 · VCV1908014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2764 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0343%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2764	likely benign
REVEL	0.571	indeterminate
SaProt	LLR -14.80	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.9, phastCons 1
Overall
CADD	25.5	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 0.0343% South Asian · 31/90,486 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0215%

Overall 0.00205% 33/1,610,864 alleles · ultra-rare exomes 31/1,458,640 · genomes 2/152,224 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0343%	2,919
Remaining individualsnot grpmax-eligible	0.00321%	31,165

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: C7
Protein: p.Pro681Arg
Coding: c.2042C>G
MANE Select: NM_000587
dbSNP: rs560966807
Type: single nucleotide variant
Location: chr5:40972562 (GRCh38)
Structure: AlphaFold pLDDT 89.67 · 6 PDB

Full C7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C7 c.281-1G>T Pathogenic/Likely pathogenic ★★ same type
C7 c.63-1G>A Pathogenic ★★ same type
C7 c.739-2A>G Likely pathogenic ★★ same type
C7 p.Arg402Ter Pathogenic/Likely pathogenic ★★ same type
C7 p.Gln271Ter Pathogenic/Likely pathogenic ★★ same type
C7 p.Gly379Arg Pathogenic/Likely pathogenic ★★ same type
C7 p.Trp205Ter Pathogenic/Likely pathogenic ★★ same type
C7 p.Ala359Thr 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/c7-p-pro681arg (accessed [today's date]).

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