Is C8A p.Gln518His (c.1554G>C) pathogenic?

C8A p.Gln518His (c.1554G>C) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). AlphaMissense: likely benign (0.2276); Absent from gnomAD v4.1.

How common is C8A p.Gln518His (c.1554G>C) in the general population?

C8A p.Gln518His (c.1554G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C8A p.Gln518His (c.1554G>C)?

AlphaMissense predicts likely benign (score 0.2276) — an in-silico prediction, not a clinical call.

C8A p.Gln518His

c.1554G>C · rs2522619604 · VCV1713392

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2276 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2276	likely benign
REVEL	0.455	indeterminate
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	20.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C8A
Protein: p.Gln518His
Coding: c.1554G>C
MANE Select: NM_000562
dbSNP: rs2522619604
Type: single nucleotide variant
Location: chr1:56912576 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 518: the egf-like domain; a disulfide bond; a UniProt-annotated variant site (in c8d1)

Full C8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8A p.Arg424Ter Pathogenic ★★ same type
C8A p.Arg498Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Glu466Ter Pathogenic ★★ same type
C8A p.Tyr210Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Tyr384Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Arg107Cys Uncertain significance ★★ ⚠ same type
C8A p.Arg196His Uncertain significance ★★ ⚠ same type
C8A p.Arg207Gln 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/c8a-p-gln518his (accessed [today's date]).

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