Is C8A p.Pro475Leu (c.1424C>T) pathogenic?

C8A p.Pro475Leu (c.1424C>T) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). AlphaMissense: likely benign (0.0855); Very rare (popmax 0.00167%, amr).

How common is C8A p.Pro475Leu (c.1424C>T) in the general population?

C8A p.Pro475Leu (c.1424C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about C8A p.Pro475Leu (c.1424C>T)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

C8A p.Pro475Leu

c.1424C>T · rs143256214 · VCV2315445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -3.41	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 0.54	GERP -3.2
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	11.36	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 0.00167% Admixed American · 1/60,008 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00062% 10/1,614,098 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Admixed Americangrpmax	0.00167%	60,008
European (non-Finnish)	0.000254%	393,348

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro475Leu
Coding: c.1424C>T
MANE Select: NM_000562
dbSNP: rs143256214
Type: single nucleotide variant
Location: chr1:56912446 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 475: a UniProt-annotated variant site (in c8d1); the macpf domain

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

Similar variants

C8A p.Pro475Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
C8A p.Pro475fs Pathogenic ★ 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

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-pro475leu (accessed [today's date]).

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