Is C8A p.Glu561Gln (c.1681G>C) pathogenic?

C8A p.Glu561Gln (c.1681G>C) is classified Benign/Likely benign in C8A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0777); Common (popmax 22.1%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C8A p.Glu561Gln (c.1681G>C)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

C8A p.Glu561Gln

Q: How common is C8A p.Glu561Gln (c.1681G>C) in the general population?

C8A p.Glu561Gln (c.1681G>C) is common (popmax 22.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1681G>C · rs1342440 · VCV402464

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 22.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -7.74	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 3.5	GERP 0.29, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	11.15	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 22.1% African / African-American · 16,577/75,010 alleles

Filtering AF 21.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.7%

Overall 6.2% 100,116/1,614,138 alleles · common exomes 84,516/1,461,860 · genomes 15,600/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	22.1%	5
South Asian	13.3%	8
Middle Eastern	11.2%	9
Admixed American	9.67%	10
Remaining individualsnot grpmax-eligible	6.9%	14
East Asian	6.35%	16
Amishnot grpmax-eligible	4.82%	21
Finnishnot grpmax-eligible	4.61%	22
European (non-Finnish)	4.54%	22
Ashkenazi Jewishnot grpmax-eligible	4.29%	23

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: C8A
Protein: p.Glu561Gln
Coding: c.1681G>C
MANE Select: NM_000562
dbSNP: rs1342440
Type: single nucleotide variant
Location: chr1:56917642 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 561: the tsp type-1 2 domain; a UniProt-annotated variant site (in c8d1); a UniProt-annotated variant site (in)

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

Similar variants

C8A p.Glu561= Likely benign ★ same residue
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

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-glu561gln (accessed [today's date]).

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