Is NACA p.Cys49Phe (c.146G>T) pathogenic?

NACA p.Cys49Phe (c.146G>T) is classified Uncertain significance in NACA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.1507); Ultra-rare (popmax 0.0173%, mid).

How common is NACA p.Cys49Phe (c.146G>T) in the general population?

NACA p.Cys49Phe (c.146G>T) is ultra-rare (popmax 0.0173%, mid) (gnomAD).

What do computational predictors say about NACA p.Cys49Phe (c.146G>T)?

AlphaMissense predicts likely benign (score 0.1507) — an in-silico prediction, not a clinical call.

NACA p.Cys49Phe

c.146G>T · VCV3402454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1507 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1507	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -5.71	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 -0.11	GERP -2.5, phastCons 0.079
Regional constraint	o/e 1.03	unconstrained · MANE · 5,320 bp · p 0.34 · regional, not allelic
Overall
CADD	13.88	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 0.0173% Middle Eastern · 1/5,770 alleles

Filtering AF 0.00125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00213% 33/1,550,618 alleles · ultra-rare exomes 33/1,405,386 · genomes 0/145,232 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0173%	5,770
Remaining individualsnot grpmax-eligible	0.00669%	14,945
Ashkenazi Jewishnot grpmax-eligible	0.00384%	26,050
African / African-American	0.00284%	35,229
South Asian	0.00239%	41,780
European (non-Finnish)	0.00191%	52,344
Finnishnot grpmax-eligible	0.00171%	58,362

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.Cys49Phe
Coding: c.146G>T
MANE Select: NM_001365896
Type: single nucleotide variant
Location: chr12:56721384 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 38.15 · 26 PDB
Residue 49: the 'disordered' region

Full NACA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NACA p.Cys49Ser Uncertain significance ★ ⚠ same residue
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

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-cys49phe (accessed [today's date]).

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