Is NACA p.Phe405Ser (c.1214T>C) pathogenic?

NACA p.Phe405Ser (c.1214T>C) is classified Benign in NACA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-01-10). AlphaMissense: likely benign (0.0593); Common (popmax 90.4%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about NACA p.Phe405Ser (c.1214T>C)?

AlphaMissense predicts likely benign (score 0.0593) — an in-silico prediction, not a clinical call.

NACA p.Phe405Ser

Q: How common is NACA p.Phe405Ser (c.1214T>C) in the general population?

NACA p.Phe405Ser (c.1214T>C) is common (popmax 90.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1214T>C · rs2926743 · VCV1260078

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0593 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 90.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0593	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -3.54	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 2.9	GERP -1.4, phastCons 0.22
Regional constraint	o/e 1.03	unconstrained · MANE · 5,320 bp · p 0.34 · regional, not allelic
Overall
CADD	4.747	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 90.4% African / African-American · 67,745/74,948 alleles

Filtering AF 89.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 89.6%

Overall 74.4% 1,200,798/1,613,518 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	90.4%	1
South Asian	82.9%	1
Admixed American	80.5%	1
Finnishnot grpmax-eligible	79.7%	1
Amishnot grpmax-eligible	79.3%	1
Remaining individualsnot grpmax-eligible	74.2%	1
European (non-Finnish)	72.5%	1
Middle Eastern	72%	1
Ashkenazi Jewishnot grpmax-eligible	70.1%	1
East Asian	70%	1

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.Phe405Ser
Coding: c.1214T>C
MANE Select: NM_001365896
dbSNP: rs2926743
Type: single nucleotide variant
Location: chr12:56720316 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 38.15 · 26 PDB
Residue 405: a UniProt-annotated variant site (in)

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

Similar variants

NACA p.Ala242= 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
NACA p.Ala348Ser 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-phe405ser (accessed [today's date]).

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