Is C8A p.Arg485His (c.1454G>A) pathogenic?

C8A p.Arg485His (c.1454G>A) is classified Benign in C8A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0948); Low-frequency (popmax 2.47%, mid).

How common is C8A p.Arg485His (c.1454G>A) in the general population?

C8A p.Arg485His (c.1454G>A) is low-frequency (popmax 2.47%, mid) (gnomAD).

What do computational predictors say about C8A p.Arg485His (c.1454G>A)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

C8A p.Arg485His

c.1454G>A · rs1620075 · VCV710241

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.47%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -10.71	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -4
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	11.42	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 2.47% Middle Eastern · 150/6,062 alleles

Filtering AF 2.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.03%

Overall 0.128% 2,067/1,614,144 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.47%	40
Ashkenazi Jewishnot grpmax-eligible	0.885%	113
South Asian	0.371%	269
Remaining individualsnot grpmax-eligible	0.283%	353
Admixed American	0.235%	426
European (non-Finnish)	0.0815%	1,227
African / African-American	0.0427%	2,344
East Asian	0.00891%	11,218
Finnishnot grpmax-eligible	0.00156%	64,038

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.Arg485His
Coding: c.1454G>A
MANE Select: NM_000562
dbSNP: rs1620075
Type: single nucleotide variant
Location: chr1:56912476 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 485: a UniProt-annotated variant site (in c8d1); a UniProt-annotated variant site (in); the macpf domain; an α-helix

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

Similar variants

C8A p.Arg485= Benign/Likely benign ★★ same residue
C8A p.Arg485Cys Uncertain significance ★ ⚠ same residue
C8A p.Arg485Leu 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

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-arg485his (accessed [today's date]).

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