Is C8A p.Pro34Ser (c.100C>T) pathogenic?

C8A p.Pro34Ser (c.100C>T) is classified Benign/Likely benign in C8A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1164); Common (popmax 10.6%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C8A p.Pro34Ser (c.100C>T)?

AlphaMissense predicts likely benign (score 0.1164) — an in-silico prediction, not a clinical call.

C8A p.Pro34Ser

Q: How common is C8A p.Pro34Ser (c.100C>T) in the general population?

C8A p.Pro34Ser (c.100C>T) is common (popmax 10.6%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.100C>T · rs143523574 · VCV1169492

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1164 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.6%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1164	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -9.36	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 0.22	GERP -4.2
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	4.26	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 10.6% Admixed American · 6,369/59,958 alleles

Filtering AF 10.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.3%

Overall 0.44% 7,102/1,613,714 alleles · common exomes 5,921/1,461,434 · genomes 1,181/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	10.6%	9
Remaining individualsnot grpmax-eligible	0.373%	268
African / African-American	0.187%	536
Finnishnot grpmax-eligible	0.0375%	2,667
European (non-Finnish)	0.0281%	3,564
Middle Eastern	0.0165%	6,062
East Asian	0.00446%	22,431
South Asian	0.0022%	45,534

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.Pro34Ser
Coding: c.100C>T
MANE Select: NM_000562
dbSNP: rs143523574
Type: single nucleotide variant
Location: chr1:56867631 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 34: an α-helix

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

Similar variants

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
C8A p.Arg207Gln 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-pro34ser (accessed [today's date]).

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