Is NLRC4 p.Cys495Tyr (c.1484G>A) pathogenic?

NLRC4 p.Cys495Tyr (c.1484G>A) is classified Uncertain significance in NLRC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-09-15). AlphaMissense: likely pathogenic (0.814); Very rare (popmax 8.47e-05%, nfe).

How common is NLRC4 p.Cys495Tyr (c.1484G>A) in the general population?

NLRC4 p.Cys495Tyr (c.1484G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about NLRC4 p.Cys495Tyr (c.1484G>A)?

AlphaMissense predicts likely pathogenic (score 0.814) — an in-silico prediction, not a clinical call.

NLRC4 p.Cys495Tyr

c.1484G>A · rs777295321 · VCV808726

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.814	likely pathogenic · top 7% in NLRC4
REVEL	0.227	benign-leaning
SaProt	LLR -16.48	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.86, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 32 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	22.1	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 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 0.000657% 1/152,182 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: NLRC4
Protein: p.Cys495Tyr
Coding: c.1484G>A
MANE Select: NM_001199138
dbSNP: rs777295321
Type: single nucleotide variant
Location: chr2:32250380 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.18 · 6 PDB

Full NLRC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NLRC4 p.Ser445Pro Pathogenic/Likely pathogenic ★★ ⚠ same type
NLRC4 p.Val341Ala Pathogenic ★★ ⚠ same type
NLRC4 c.2258-3C>G Uncertain significance ★★ same type
NLRC4 c.2351-8T>G Uncertain significance ★★ same type
NLRC4 p.Ala1018Thr Uncertain significance ★★ ⚠ same type
NLRC4 p.Ala193Pro Uncertain significance ★★ ⚠ same type
NLRC4 p.Ala234Val Uncertain significance ★★ ⚠ same type
NLRC4 p.Ala318Pro 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/nlrc4-p-cys495tyr (accessed [today's date]).

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