Is CARD19 p.Arg59Ser (c.175C>A) pathogenic?

CARD19 p.Arg59Ser (c.175C>A) is classified Uncertain significance in CARD19 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-06). AlphaMissense: likely pathogenic (0.6515); Very rare (popmax 0.00167%, amr).

How common is CARD19 p.Arg59Ser (c.175C>A) in the general population?

CARD19 p.Arg59Ser (c.175C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CARD19 p.Arg59Ser (c.175C>A)?

AlphaMissense predicts likely pathogenic (score 0.6515) — an in-silico prediction, not a clinical call.

CARD19 p.Arg59Ser

c.175C>A · rs201271055 · VCV2287908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6515 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6515	likely pathogenic
REVEL	0.149	moderately benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 17 kb · p 0.69 · regional, not allelic
Overall
CADD	18.48	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 0.00167% Admixed American · 1/59,882 alleles

Overall 6.86e-05% 1/1,457,888 alleles · very rare

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: CARD19
Protein: p.Arg59Ser
Coding: c.175C>A
MANE Select: NM_032310
dbSNP: rs201271055
Type: single nucleotide variant
Location: chr9:93110592 (GRCh38)
Gene constraint: LOEUF 1.565 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.51 · 2 PDB
Residue 59: the card domain; an α-helix; a disulfide bond

Full CARD19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CARD19 p.Arg59Cys Uncertain significance ★ ⚠ same residue
CARD19 p.Ala83Asp Uncertain significance ★ ⚠ same type
CARD19 p.Arg121Lys Uncertain significance ★ same type
CARD19 p.Arg155Ser Uncertain significance ★ same type
CARD19 p.Arg166Thr Uncertain significance ★ same type
CARD19 p.Arg170His Uncertain significance ★ same type
CARD19 p.Arg170Pro Uncertain significance ★ same type
CARD19 p.Arg22Cys 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/card19-p-arg59ser (accessed [today's date]).

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