Is C8A p.Lys214Arg (c.641A>G) pathogenic?

C8A p.Lys214Arg (c.641A>G) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely benign (0.0854); Very rare (popmax 0.00288%, nfe).

How common is C8A p.Lys214Arg (c.641A>G) in the general population?

C8A p.Lys214Arg (c.641A>G) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about C8A p.Lys214Arg (c.641A>G)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

C8A p.Lys214Arg

c.641A>G · rs374344050 · VCV3136081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.43	donor gain · deltas
Pangolin	Δ0.44	gain · loss 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2	GERP -1.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	15.87	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 0.00288% European (non-Finnish) · 34/1,179,702 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00217% 35/1,613,198 alleles · very rare exomes 35/1,460,878 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,697
Remaining individualsnot grpmax-eligible	0.0016%	62,438

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.Lys214Arg
Coding: c.641A>G
MANE Select: NM_000562
dbSNP: rs374344050
Type: single nucleotide variant
Location: chr1:56881621 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 214: a β-strand; the macpf domain

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-lys214arg (accessed [today's date]).

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