Is C8A p.Pro575Leu (c.1724C>T) pathogenic?

C8A p.Pro575Leu (c.1724C>T) is classified Benign/Likely benign in C8A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0743); Common (popmax 12.9%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C8A p.Pro575Leu (c.1724C>T)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

C8A p.Pro575Leu

Q: How common is C8A p.Pro575Leu (c.1724C>T) in the general population?

C8A p.Pro575Leu (c.1724C>T) is common (popmax 12.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1724C>T · rs17300936 · VCV1166647

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.9%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.45	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 -0.008	GERP -0.71
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	12.39	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 12.9% European (non-Finnish) · 152,765/1,179,946 alleles

Filtering AF 12.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.9%

Overall 11.4% 184,170/1,614,016 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	15%	7
European (non-Finnish)grpmax	12.9%	8
Finnishnot grpmax-eligible	11%	9
Remaining individualsnot grpmax-eligible	10.9%	9
South Asian	7.65%	13
Ashkenazi Jewishnot grpmax-eligible	7.1%	14
East Asian	6.88%	15
Middle Eastern	5.72%	17
Admixed American	4.3%	23
African / African-American	3.08%	32

Amish 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.Pro575Leu
Coding: c.1724C>T
MANE Select: NM_000562
dbSNP: rs17300936
Type: single nucleotide variant
Location: chr1:56917685 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 575: the tsp type-1 2 domain; the 'disordered' region; a disulfide bond; a UniProt-annotated variant site (in c8d1); a UniProt-annotated variant site (in)

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

Similar variants

C8A p.Pro575Ser Benign/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-pro575leu (accessed [today's date]).

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