Is C8A p.Asp243Gly (c.728A>G) pathogenic?

C8A p.Asp243Gly (c.728A>G) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-17). AlphaMissense: likely benign (0.0891); Ultra-rare (popmax 0.0283%, amr).

How common is C8A p.Asp243Gly (c.728A>G) in the general population?

C8A p.Asp243Gly (c.728A>G) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about C8A p.Asp243Gly (c.728A>G)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

C8A p.Asp243Gly

c.728A>G · rs746314925 · VCV1408286

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.76	donor gain · deltas
Pangolin	Δ0.42	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2	GERP -4.3, phastCons 0.007
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	21.7	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 0.0283% Admixed American · 17/59,972 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00116% 17/1,461,698 alleles · ultra-rare

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.Asp243Gly
Coding: c.728A>G
MANE Select: NM_000562
dbSNP: rs746314925
Type: single nucleotide variant
Location: chr1:56883554 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 243: an α-helix; the macpf domain

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

Similar variants

C8A p.Asp243= 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-asp243gly (accessed [today's date]).

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