Is NAA15 p.Ser778Phe (c.2333C>T) pathogenic?

NAA15 p.Ser778Phe (c.2333C>T) is classified Uncertain significance in NAA15 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-08). AlphaMissense: likely benign (0.1284); Very rare (popmax 0.00134%, afr); Associated with intellectual disability, autosomal dominant 50.

What condition is associated with NAA15 p.Ser778Phe (c.2333C>T)?

NAA15 p.Ser778Phe (c.2333C>T) is associated with intellectual disability, autosomal dominant 50 (ClinVar).

How common is NAA15 p.Ser778Phe (c.2333C>T) in the general population?

NAA15 p.Ser778Phe (c.2333C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about NAA15 p.Ser778Phe (c.2333C>T)?

AlphaMissense predicts likely benign (score 0.1284) — an in-silico prediction, not a clinical call.

NAA15 p.Ser778Phe

c.2333C>T · rs747017034 · VCV1683738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1284 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

intellectual disability, autosomal dominant 50

Computational evidence

Protein change
AlphaMissense	0.1284	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -12.30	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 26 kb · p 6.2e-07 · regional, not allelic
Overall
CADD	27.8	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 0.00134% African / African-American · 1/74,818 alleles

Overall 6.21e-05% 1/1,609,016 alleles · very rare exomes 1/1,456,714 · genomes 0/152,302 · 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: NAA15
Protein: p.Ser778Phe
Coding: c.2333C>T
MANE Select: NM_057175
dbSNP: rs747017034
Type: single nucleotide variant
Location: chr4:139386163 (GRCh38)
Gene constraint: LOEUF 0.438 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 89.66 · 12 PDB
Residue 778: an α-helix; a UniProt-annotated variant site (in mrd50); the 'interaction with hypk' region

Full NAA15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal dominant 50 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NAA15 p.Ser778Cys Uncertain significance ★ ⚠ same residue
NAA15 c.1539+1G>A Pathogenic/Likely pathogenic ★★ same condition
NAA15 c.1753+1G>T Pathogenic/Likely pathogenic ★★ same condition
NAA15 c.908-2A>G Pathogenic ★★ same condition
NAA15 p.Ala585Thr Likely pathogenic ★★ ⚠ same condition
NAA15 p.Arg128Ter Pathogenic ★★ same condition
NAA15 p.Arg144Ter Pathogenic ★★ same condition
NAA15 p.Arg549Ter Pathogenic/Likely pathogenic ★★ same condition

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/naa15-p-ser778phe (accessed [today's date]).

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