Is NACA p.Ala372Val (c.1115C>T) pathogenic?

NACA p.Ala372Val (c.1115C>T) is classified Uncertain significance in NACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1887); Ultra-rare (popmax 0.0445%, eas).

How common is NACA p.Ala372Val (c.1115C>T) in the general population?

NACA p.Ala372Val (c.1115C>T) is ultra-rare (popmax 0.0445%, eas) (gnomAD).

What do computational predictors say about NACA p.Ala372Val (c.1115C>T)?

AlphaMissense predicts likely benign (score 0.1887) — an in-silico prediction, not a clinical call.

NACA p.Ala372Val

c.1115C>T · rs760903215 · VCV2550546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1887 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0445%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1887	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -7.34	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 1.4	GERP -2.4, phastCons 0.007
Regional constraint	o/e 1.03	unconstrained · MANE · 5,320 bp · p 0.34 · regional, not allelic
Overall
CADD	10.82	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

Grpmax group 0.0445% East Asian · 20/44,894 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00136% 22/1,613,784 alleles · ultra-rare exomes 20/1,461,586 · genomes 2/152,198 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0445%	2,245
Remaining individualsnot grpmax-eligible	0.0016%	62,464
European (non-Finnish)	8.48e-05%	1,179,830

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.Ala372Val
Coding: c.1115C>T
MANE Select: NM_001365896
dbSNP: rs760903215
Type: single nucleotide variant
Location: chr12:56720415 (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.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-ala372val (accessed [today's date]).

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