Is C8A p.Leu9Ser (c.26T>C) pathogenic?

C8A p.Leu9Ser (c.26T>C) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely benign (0.1653); Rare (popmax 0.858%, eas).

How common is C8A p.Leu9Ser (c.26T>C) in the general population?

C8A p.Leu9Ser (c.26T>C) is rare (popmax 0.858%, eas) (gnomAD).

What do computational predictors say about C8A p.Leu9Ser (c.26T>C)?

AlphaMissense predicts likely benign (score 0.1653) — an in-silico prediction, not a clinical call.

C8A p.Leu9Ser

c.26T>C · rs192696675 · VCV1434605

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1653 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.858%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1653	likely benign
REVEL	0.467	indeterminate
SaProt	LLR -7.32	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 2.7	GERP -0.24, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	23.0	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 0.858% East Asian · 385/44,872 alleles

Filtering AF 0.787% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.76%

Overall 0.024% 388/1,613,802 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.858%	117
Remaining individualsnot grpmax-eligible	0.0032%	31,247
Admixed American	0.00167%	59,968

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.Leu9Ser
Coding: c.26T>C
MANE Select: NM_000562
dbSNP: rs192696675
Type: single nucleotide variant
Location: chr1:56854927 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB

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-leu9ser (accessed [today's date]).

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