Is NAF1 p.Ser488Pro (c.1462T>C) pathogenic?

NAF1 p.Ser488Pro (c.1462T>C) is classified Uncertain significance in NAF1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-05-18). AlphaMissense: likely benign (0.0879); Very rare (popmax 0.000179%, nfe).

How common is NAF1 p.Ser488Pro (c.1462T>C) in the general population?

NAF1 p.Ser488Pro (c.1462T>C) is very rare (popmax 0.000179%, nfe) (gnomAD).

What do computational predictors say about NAF1 p.Ser488Pro (c.1462T>C)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

NAF1 p.Ser488Pro

c.1462T>C · rs1730751955 · VCV2443186

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000179%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.77	GERP -1.3, phastCons 0.28
Overall
CADD	14.93	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 0.000179% European (non-Finnish) · 2/1,118,822 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000133% 2/1,505,038 alleles · very rare exomes 1/1,361,380 · genomes 1/143,658 · joint denominator

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: NAF1
Protein: p.Ser488Pro
Coding: c.1462T>C
MANE Select: NM_138386
dbSNP: rs1730751955
Type: single nucleotide variant
Location: chr4:163128920 (GRCh38)
Structure: AlphaFold pLDDT 72.47 · 8 PDB
Residue 488: the 'required for inhibitory activity of tnf-induced nf-kappa-b activation' region; an α-helix; the 'ubiquitin-binding domain (ubd)' region

Full NAF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NAF1 p.Ala102Ser Uncertain significance ★★ ⚠ same type
NAF1 p.Ala323Val Uncertain significance ★★ ⚠ same type
NAF1 p.Ala87Val Uncertain significance ★★ ⚠ same type
NAF1 p.Arg106Trp Uncertain significance ★★ ⚠ same type
NAF1 p.Arg437Cys Uncertain significance ★★ ⚠ same type
NAF1 p.Arg437His Uncertain significance ★★ ⚠ same type
NAF1 p.Asn17Ser Uncertain significance ★★ ⚠ same type
NAF1 p.Asp109Tyr 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/naf1-p-ser488pro (accessed [today's date]).

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