Is C8A p.Leu510Phe (c.1528C>T) pathogenic?

C8A p.Leu510Phe (c.1528C>T) is classified Uncertain significance in C8A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-15). AlphaMissense: likely benign (0.2371); Ultra-rare (popmax 0.0524%, nfe).

How common is C8A p.Leu510Phe (c.1528C>T) in the general population?

C8A p.Leu510Phe (c.1528C>T) is ultra-rare (popmax 0.0524%, nfe) (gnomAD).

What do computational predictors say about C8A p.Leu510Phe (c.1528C>T)?

AlphaMissense predicts likely benign (score 0.2371) — an in-silico prediction, not a clinical call.

C8A p.Leu510Phe

c.1528C>T · rs200018561 · VCV1053353

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2371 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0524%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2371	likely benign
REVEL	0.633	indeterminate
SaProt	LLR -8.69	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 2.1	GERP 0.31, phastCons 0.98
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	21.8	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 0.0524% European (non-Finnish) · 618/1,180,028 alleles

Filtering AF 0.0489% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0476%

Overall 0.0395% 637/1,614,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0524%	1,909
Remaining individualsnot grpmax-eligible	0.0208%	4,807
African / African-American	0.00534%	18,734
Admixed American	0.00333%	30,007

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.Leu510Phe
Coding: c.1528C>T
MANE Select: NM_000562
dbSNP: rs200018561
Type: single nucleotide variant
Location: chr1:56912550 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 510: the egf-like domain; a β-strand; a disulfide bond; a UniProt-annotated variant site (in c8d1)

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-leu510phe (accessed [today's date]).

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