Is NAF1 p.Pro99Ser (c.295C>T) pathogenic?

NAF1 p.Pro99Ser (c.295C>T) is classified Uncertain significance in NAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0693); Very rare (popmax 0.00134%, afr).

How common is NAF1 p.Pro99Ser (c.295C>T) in the general population?

NAF1 p.Pro99Ser (c.295C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about NAF1 p.Pro99Ser (c.295C>T)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

NAF1 p.Pro99Ser

c.295C>T · rs758040980 · VCV2987474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -6.48	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 0.45	GERP -0.48
Overall
CADD	4.976	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 0.00134% African / African-American · 1/74,868 alleles

Filtering AF 0.00069% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00054%

Overall 0.000933% 15/1,607,962 alleles · very rare exomes 15/1,455,608 · genomes 0/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,868
European (non-Finnish)	0.00119%	84,084

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.Pro99Ser
Coding: c.295C>T
MANE Select: NM_138386
dbSNP: rs758040980
Type: single nucleotide variant
Location: chr4:163166433 (GRCh38)
Structure: AlphaFold pLDDT 72.47 · 8 PDB
Residue 99: the 'disordered' region; the 'interaction with nef' region

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

Similar variants

NAF1 p.Pro99Ala Uncertain significance ★ ⚠ same residue
NAF1 p.Pro99Thr Uncertain significance ★ ⚠ same residue
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

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-pro99ser (accessed [today's date]).

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