Is NAAA p.Leu162Phe (c.486A>T) pathogenic?

NAAA p.Leu162Phe (c.486A>T) is classified Uncertain significance in NAAA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-19). AlphaMissense: likely benign (0.118); Absent from gnomAD v4.1.

How common is NAAA p.Leu162Phe (c.486A>T) in the general population?

NAAA p.Leu162Phe (c.486A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NAAA p.Leu162Phe (c.486A>T)?

AlphaMissense predicts likely benign (score 0.118) — an in-silico prediction, not a clinical call.

NAAA p.Leu162Phe

c.486A>T · rs2476257604 · VCV2336877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.118 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.118	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -7.17	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 0.016	GERP 0.6, phastCons 0.95
Regional constraint	o/e 0.98	unconstrained · MANE · 26 kb · p 0.72 · regional, not allelic
Overall
CADD	21.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NAAA
Protein: p.Leu162Phe
Coding: c.486A>T
MANE Select: NM_014435
dbSNP: rs2476257604
Type: single nucleotide variant
Location: chr4:75936121 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.67 · 2 PDB
Residue 162: a β-strand

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

Similar variants

NAAA c.667-7C>T Benign ★★ same type
NAAA p.Ile80= Likely benign ★★ same type
NAAA p.Thr262= Benign ★★ same type
NAAA p.Ala119Asp Uncertain significance ★ ⚠ same type
NAAA p.Ala314Val Uncertain significance ★ ⚠ same type
NAAA p.Arg100His Uncertain significance ★ ⚠ same type
NAAA p.Arg196Gln Uncertain significance ★ ⚠ same type
NAAA p.Arg256Trp 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/naaa-p-leu162phe (accessed [today's date]).

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