Is NACA p.Asp654Glu (c.1962C>A) pathogenic?

NACA p.Asp654Glu (c.1962C>A) is classified Uncertain significance in NACA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely benign (0.1818); Very rare (popmax 0.000848%, nfe).

How common is NACA p.Asp654Glu (c.1962C>A) in the general population?

NACA p.Asp654Glu (c.1962C>A) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about NACA p.Asp654Glu (c.1962C>A)?

AlphaMissense predicts likely benign (score 0.1818) — an in-silico prediction, not a clinical call.

NACA p.Asp654Glu

c.1962C>A · VCV3402453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1818	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.18	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 0.29	GERP -2.4
Regional constraint	o/e 1.03	unconstrained · MANE · 5,320 bp · p 0.34 · regional, not allelic
Overall
CADD	9.566	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 0.000848% European (non-Finnish) · 10/1,179,872 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000744% 12/1,613,922 alleles · very rare exomes 12/1,461,588 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,969
European (non-Finnish)grpmax	0.000848%	117,987

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.Asp654Glu
Coding: c.1962C>A
MANE Select: NM_001365896
Type: single nucleotide variant
Location: chr12:56719568 (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-asp654glu (accessed [today's date]).

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