Is NACA p.Pro490Arg (c.1469C>G) pathogenic?

NACA p.Pro490Arg (c.1469C>G) is classified Benign in NACA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-21). AlphaMissense: likely benign (0.1189); Low-frequency (popmax 4.86%, afr).

How common is NACA p.Pro490Arg (c.1469C>G) in the general population?

NACA p.Pro490Arg (c.1469C>G) is low-frequency (popmax 4.86%, afr) (gnomAD).

What do computational predictors say about NACA p.Pro490Arg (c.1469C>G)?

AlphaMissense predicts likely benign (score 0.1189) — an in-silico prediction, not a clinical call.

NACA p.Pro490Arg

c.1469C>G · rs11834498 · VCV768556

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1189 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.86%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1189	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -8.72	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 1.2	GERP -2.2, phastCons 0.45
Regional constraint	o/e 1.03	unconstrained · MANE · 5,320 bp · p 0.34 · regional, not allelic
Overall
CADD	16.39	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 4.86% African / African-American · 3,640/74,958 alleles

Filtering AF 4.72% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.67%

Overall 0.253% 4,089/1,613,880 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.86%	21
Admixed American	0.335%	299
Remaining individualsnot grpmax-eligible	0.317%	316
Middle Eastern	0.247%	404
South Asian	0.00329%	30,363
European (non-Finnish)	0.00271%	36,871

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: NACA
Protein: p.Pro490Arg
Coding: c.1469C>G
MANE Select: NM_001365896
dbSNP: rs11834498
Type: single nucleotide variant
Location: chr12:56720061 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 38.15 · 26 PDB

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

Similar variants

NACA p.Ala242= Benign ★★ same type
NACA p.Phe405Ser Benign ★★ same type
NACA p.Pro1772Ser Benign ★★ same type
NACA p.Ala152Val Uncertain significance ★ ⚠ same type
NACA p.Ala1803Pro Uncertain significance ★ ⚠ same type
NACA p.Ala1833Val Uncertain significance ★ ⚠ same type
NACA p.Ala1868Val Uncertain significance ★ ⚠ same type
NACA p.Ala348Ser 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/naca-p-pro490arg (accessed [today's date]).

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