Is NAAA p.Pro94His (c.281C>A) pathogenic?

NAAA p.Pro94His (c.281C>A) is classified Uncertain significance in NAAA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-13). AlphaMissense: likely benign (0.2368); Absent from gnomAD v4.1.

How common is NAAA p.Pro94His (c.281C>A) in the general population?

NAAA p.Pro94His (c.281C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NAAA p.Pro94His (c.281C>A)?

AlphaMissense predicts likely benign (score 0.2368) — an in-silico prediction, not a clinical call.

NAAA p.Pro94His

c.281C>A · rs187885550 · VCV2283582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2368 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2368	likely benign
REVEL	0.3	indeterminate
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP -0.44, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 26 kb · p 0.72 · regional, not allelic
Overall
CADD	24.4	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.Pro94His
Coding: c.281C>A
MANE Select: NM_014435
dbSNP: rs187885550
Type: single nucleotide variant
Location: chr4:75940091 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.67 · 2 PDB

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-pro94his (accessed [today's date]).

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