Is NACA p.Pro1818Leu (c.5453C>T) pathogenic?

NACA p.Pro1818Leu (c.5453C>T) is classified Likely benign in NACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.17); Rare (popmax 0.657%, eas).

How common is NACA p.Pro1818Leu (c.5453C>T) in the general population?

NACA p.Pro1818Leu (c.5453C>T) is rare (popmax 0.657%, eas) (gnomAD).

What do computational predictors say about NACA p.Pro1818Leu (c.5453C>T)?

AlphaMissense predicts likely benign (score 0.17) — an in-silico prediction, not a clinical call.

NACA p.Pro1818Leu

c.5453C>T · VCV4555692

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.17 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.657%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.17	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	GERP -1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 3,084 bp · p 0.49 · regional, not allelic
Overall
CADD	17.69	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 0.657% East Asian · 295/44,876 alleles

Filtering AF 0.596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.572%

Overall 0.0227% 366/1,612,904 alleles · rare exomes 343/1,460,648 · genomes 23/152,256 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.657%	152
Admixed American	0.00834%	11,994
Remaining individualsnot grpmax-eligible	0.00801%	12,490
European (non-Finnish)	0.00492%	20,333
South Asian	0.0022%	45,517
African / African-American	0.00133%	75,006

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.Pro1818Leu
Coding: c.5453C>T
MANE Select: NM_001365896
Type: single nucleotide variant
Location: chr12:56716077 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 38.15 · 26 PDB
Residue 1818: 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-pro1818leu (accessed [today's date]).

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