Is NLRP14 p.Ser4Thr (c.10T>A) pathogenic?

NLRP14 p.Ser4Thr (c.10T>A) is classified Uncertain significance in NLRP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: likely benign (0.0719); Ultra-rare (popmax 0.0752%, nfe).

How common is NLRP14 p.Ser4Thr (c.10T>A) in the general population?

NLRP14 p.Ser4Thr (c.10T>A) is ultra-rare (popmax 0.0752%, nfe) (gnomAD).

What do computational predictors say about NLRP14 p.Ser4Thr (c.10T>A)?

AlphaMissense predicts likely benign (score 0.0719) — an in-silico prediction, not a clinical call.

NLRP14 p.Ser4Thr

c.10T>A · rs149195401 · VCV2346220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0752%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0719	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.15	GERP -1.3
Regional constraint	o/e 1.09	unconstrained · MANE · 33 kb · p 0.0023 · regional, not allelic
Overall
CADD	1.125	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 0.0752% European (non-Finnish) · 887/1,179,960 alleles

Filtering AF 0.071% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0694%

Overall 0.0597% 963/1,613,830 alleles · ultra-rare exomes 892/1,461,492 · genomes 71/152,338 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0752%	1,330
Admixed American	0.0583%	1,715
African / African-American	0.0293%	3,411
Remaining individualsnot grpmax-eligible	0.024%	4,165
Finnishnot grpmax-eligible	0.00312%	32,024
South Asian	0.0022%	45,529

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: NLRP14
Protein: p.Ser4Thr
Coding: c.10T>A
MANE Select: NM_176822
dbSNP: rs149195401
Type: single nucleotide variant
Location: chr11:7038596 (GRCh38)
Gene constraint: LOEUF 1.179 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.47 · 4 PDB
Residue 4: the pyrin domain

Full NLRP14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RBMXL2 p.Ala4= Benign ★★ same residue
RBMXL2 p.Ala4Gly Uncertain significance ★ ⚠ same residue
RBMXL2 p.Asp128Val Uncertain significance ★★ ⚠ same type
NLRP14 c.1958+74C>A Benign ★★ same type
NLRP14 c.2124-36G>A Benign ★★ same type
NLRP14 c.2292-104A>C Benign ★★ same type
NLRP14 c.3146+85C>A Benign ★★ same type
NLRP14 c.361+46T>G Benign ★★ 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/nlrp14-p-ser4thr (accessed [today's date]).

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