Is NACA p.Asp342Glu (c.1026T>A) pathogenic?

NACA p.Asp342Glu (c.1026T>A) is classified Uncertain significance in NACA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.3145); Ultra-rare (popmax 0.0242%, nfe).

How common is NACA p.Asp342Glu (c.1026T>A) in the general population?

NACA p.Asp342Glu (c.1026T>A) is ultra-rare (popmax 0.0242%, nfe) (gnomAD).

What do computational predictors say about NACA p.Asp342Glu (c.1026T>A)?

AlphaMissense predicts likely benign (score 0.3145) — an in-silico prediction, not a clinical call.

NACA p.Asp342Glu

c.1026T>A · rs758661515 · VCV3172567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3145 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3145	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -6.22	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 1.1	GERP -2.5
Regional constraint	o/e 1.03	unconstrained · MANE · 5,320 bp · p 0.34 · regional, not allelic
Overall
CADD	4.631	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 0.0242% European (non-Finnish) · 286/1,179,790 alleles

Filtering AF 0.0219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.0188% 304/1,613,764 alleles · ultra-rare exomes 288/1,461,538 · genomes 16/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0242%	4,125
Remaining individualsnot grpmax-eligible	0.0144%	6,940
Admixed American	0.00833%	11,999
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00267%	37,461
Finnishnot grpmax-eligible	0.00156%	64,020

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.Asp342Glu
Coding: c.1026T>A
MANE Select: NM_001365896
dbSNP: rs758661515
Type: single nucleotide variant
Location: chr12:56720504 (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-asp342glu (accessed [today's date]).

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