Is NACA p.Pro1090= (c.3270A>C) pathogenic?

NACA p.Pro1090= (c.3270A>C) is classified Likely benign in NACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). Ultra-rare (popmax 0.0158%, eas).

How common is NACA p.Pro1090= (c.3270A>C) in the general population?

NACA p.Pro1090= (c.3270A>C) is ultra-rare (popmax 0.0158%, eas) (gnomAD).

NACA p.Pro1090=

c.3270A>C · rs768199123 · VCV3025404

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -16	GERP -1.8
Overall
CADD	1.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0158% East Asian · 3/18,966 alleles

Filtering AF 0.00703% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.005%

Overall 0.00647% 69/1,066,234 alleles · ultra-rare exomes 35/962,060 · genomes 34/104,174 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0203%	4,922
East Asiangrpmax	0.0158%	6,322
African / African-American	0.015%	6,648
South Asian	0.0145%	6,887
Admixed American	0.0137%	7,302
Remaining individualsnot grpmax-eligible	0.0085%	11,771
Ashkenazi Jewishnot grpmax-eligible	0.00848%	11,788
European (non-Finnish)	0.0049%	20,390

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1090=
Coding: c.3270A>C
MANE Select: NM_001365896
dbSNP: rs768199123
Type: single nucleotide variant
Location: chr12:56718260 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 38.15 · 26 PDB
Residue 1090: the 'disordered' region

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.Pro490Arg 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

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-pro1090 (accessed [today's date]).

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