Is NAF1 p.Pro43Ser (c.127C>T) pathogenic?

NAF1 p.Pro43Ser (c.127C>T) is classified Benign in NAF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0624); Common (popmax 9.61%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about NAF1 p.Pro43Ser (c.127C>T)?

AlphaMissense predicts likely benign (score 0.0624) — an in-silico prediction, not a clinical call.

NAF1 p.Pro43Ser

Q: How common is NAF1 p.Pro43Ser (c.127C>T) in the general population?

NAF1 p.Pro43Ser (c.127C>T) is common (popmax 9.61%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.127C>T · rs12331663 · VCV2038933

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0624 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.61%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0624	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.49	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 0.055	GERP -1.9, phastCons 0.001
Overall
CADD	3.464	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 9.61% African / African-American · 7,204/75,000 alleles

Filtering AF 9.42% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.34%

Overall 0.515% 8,296/1,610,604 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.61%	10
Admixed American	0.776%	129
Remaining individualsnot grpmax-eligible	0.628%	159
Middle Eastern	0.248%	404
South Asian	0.0187%	5,348
European (non-Finnish)	0.0174%	5,753

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: NAF1
Protein: p.Pro43Ser
Coding: c.127C>T
MANE Select: NM_006058 · reported on NM_138386
dbSNP: rs12331663
Type: single nucleotide variant
Location: chr4:163166601 (GRCh38)
Structure: AlphaFold pLDDT 72.47 · 8 PDB

Full NAF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NAF1 p.Ala102Ser Uncertain significance ★★ ⚠ same type
NAF1 p.Ala323Val Uncertain significance ★★ ⚠ same type
NAF1 p.Ala87Val Uncertain significance ★★ ⚠ same type
NAF1 p.Arg106Trp Uncertain significance ★★ ⚠ same type
NAF1 p.Arg437Cys Uncertain significance ★★ ⚠ same type
NAF1 p.Arg437His Uncertain significance ★★ ⚠ same type
NAF1 p.Asn17Ser Uncertain significance ★★ ⚠ same type
NAF1 p.Asp109Tyr 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/naf1-p-pro43ser (accessed [today's date]).

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