Is C7 p.Arg618Gln (c.1853G>A) pathogenic?

C7 p.Arg618Gln (c.1853G>A) is classified Uncertain significance in C7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). AlphaMissense: likely benign (0.0537); Ultra-rare (popmax 0.0164%, mid).

How common is C7 p.Arg618Gln (c.1853G>A) in the general population?

C7 p.Arg618Gln (c.1853G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about C7 p.Arg618Gln (c.1853G>A)?

AlphaMissense predicts likely benign (score 0.0537) — an in-silico prediction, not a clinical call.

C7 p.Arg618Gln

c.1853G>A · rs757348574 · VCV1377138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0537 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0537	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -4.27	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 0.59	GERP -4.5, phastCons 0.85
Overall
CADD	8.349	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00254% 41/1,613,596 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
South Asian	0.00549%	18,210
European (non-Finnish)	0.00271%	36,868
Admixed American	0.00167%	59,962
Remaining individualsnot grpmax-eligible	0.0016%	62,450
African / African-American	0.00134%	74,880

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.Arg618Gln
Coding: c.1853G>A
MANE Select: NM_001565 · reported on NM_000587
dbSNP: rs757348574
Type: single nucleotide variant
Location: chr5:40964844 (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 p.Arg618Trp Uncertain significance ★★ ⚠ same residue
C7 p.Arg618Pro Uncertain significance ★ ⚠ same residue
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

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-arg618gln (accessed [today's date]).

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