Is C8A p.Asp458Asn (c.1372G>A) pathogenic?

C8A p.Asp458Asn (c.1372G>A) is classified Benign/Likely benign in C8A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1426); Common (popmax 9.54%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C8A p.Asp458Asn (c.1372G>A)?

AlphaMissense predicts likely benign (score 0.1426) — an in-silico prediction, not a clinical call.

C8A p.Asp458Asn

Q: How common is C8A p.Asp458Asn (c.1372G>A) in the general population?

C8A p.Asp458Asn (c.1372G>A) is common (popmax 9.54%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1372G>A · rs17114555 · VCV777910

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1426 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.54%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1426	likely benign
REVEL	0.437	indeterminate
SaProt	LLR -6.35	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 9.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	30.0	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 9.54% African / African-American · 7,154/74,998 alleles

Filtering AF 9.35% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.28%

Overall 0.526% 8,485/1,614,044 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.54%	10
Admixed American	0.736%	136
Remaining individualsnot grpmax-eligible	0.709%	141
Middle Eastern	0.66%	151
East Asian	0.0624%	1,603
European (non-Finnish)	0.03%	3,333
South Asian	0.0242%	4,140
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803

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.Asp458Asn
Coding: c.1372G>A
MANE Select: NM_000562
dbSNP: rs17114555
Type: single nucleotide variant
Location: chr1:56908105 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 458: a UniProt-annotated variant site (in c8d1); a UniProt-annotated variant site (in); the macpf domain; a β-strand

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

Similar variants

C8A p.Asp458= 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-asp458asn (accessed [today's date]).

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