Is C8A p.Pro575Ser (c.1723C>T) pathogenic?

C8A p.Pro575Ser (c.1723C>T) is classified Benign/Likely benign in C8A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0889); Low-frequency (popmax 1.45%, nfe).

How common is C8A p.Pro575Ser (c.1723C>T) in the general population?

C8A p.Pro575Ser (c.1723C>T) is low-frequency (popmax 1.45%, nfe) (gnomAD).

What do computational predictors say about C8A p.Pro575Ser (c.1723C>T)?

AlphaMissense predicts likely benign (score 0.0889) — an in-silico prediction, not a clinical call.

C8A p.Pro575Ser

c.1723C>T · rs41285938 · VCV1166522

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0889 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.45%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0889	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -5.87	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 1.7	GERP 2.2, phastCons 0.034
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	13.16	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 1.45% European (non-Finnish) · 17,104/1,180,024 alleles

Filtering AF 1.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.42%

Overall 1.18% 19,111/1,614,162 alleles · low-frequency exomes 17,919/1,461,868 · genomes 1,192/152,294 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.45%	69
Remaining individualsnot grpmax-eligible	1.2%	83
Ashkenazi Jewishnot grpmax-eligible	1.01%	99
Admixed American	0.556%	180
Finnishnot grpmax-eligible	0.447%	224
African / African-American	0.203%	494
South Asian	0.191%	523
Middle Eastern	0.116%	863
East Asian	0.00223%	44,876

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.Pro575Ser
Coding: c.1723C>T
MANE Select: NM_000562
dbSNP: rs41285938
Type: single nucleotide variant
Location: chr1:56917684 (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 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.Pro575Leu 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-pro575ser (accessed [today's date]).

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