Is CARD16 p.Leu57Ser (c.170T>C) pathogenic?

CARD16 p.Leu57Ser (c.170T>C) is classified Uncertain significance in CARD16 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely pathogenic (0.8601); Rare (popmax 0.115%, mid).

How common is CARD16 p.Leu57Ser (c.170T>C) in the general population?

CARD16 p.Leu57Ser (c.170T>C) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about CARD16 p.Leu57Ser (c.170T>C)?

AlphaMissense predicts likely pathogenic (score 0.8601) — an in-silico prediction, not a clinical call.

CARD16 p.Leu57Ser

c.170T>C · rs201870366 · VCV3137311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8601 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8601	likely pathogenic · top 1% in CARD16
REVEL	0.328	indeterminate
SaProt	LLR -12.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	phastCons 0.091
Regional constraint	o/e 1.11	unconstrained · MANE · 1,768 bp · p 0.24 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.115% Middle Eastern · 7/6,084 alleles

Filtering AF 0.0812% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0752%

Overall 0.00905% 146/1,614,026 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
South Asian	0.0977%	1,023
Admixed American	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0096%	10,414
European (non-Finnish)	0.00288%	34,706
African / African-American	0.00267%	37,458

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: CARD16
Protein: p.Leu57Ser
Coding: c.170T>C
MANE Select: NM_052889
dbSNP: rs201870366
Type: single nucleotide variant
Location: chr11:105044496 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 64.89
Residue 57: the card domain

Full CARD16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CARD16 c.*174T>G Uncertain significance ★ ⚠ same type
CARD16 c.*186G>C Uncertain significance ★ ⚠ same type
CARD16 c.*56T>C Uncertain significance ★ ⚠ same type
CARD16 c.*61G>C Uncertain significance ★ ⚠ same type
CARD16 c.*67C>G Uncertain significance ★ ⚠ same type
CARD16 p.Ala48Ser Uncertain significance ★ ⚠ same type
CARD16 p.Arg45His Uncertain significance ★ ⚠ same type
CARD16 p.Arg55Gln 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/card16-p-leu57ser (accessed [today's date]).

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