Is NASP p.Pro314Ser (c.940C>T) pathogenic?

NASP p.Pro314Ser (c.940C>T) is classified Uncertain significance in NASP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). AlphaMissense: likely benign (0.086); Ultra-rare (popmax 0.0495%, mid).

How common is NASP p.Pro314Ser (c.940C>T) in the general population?

NASP p.Pro314Ser (c.940C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about NASP p.Pro314Ser (c.940C>T)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

NASP p.Pro314Ser

c.940C>T · rs759459986 · VCV2225527

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -5.65	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 0.41	GERP -0.4, phastCons 0.13
Regional constraint	o/e 0.99	unconstrained · MANE · 7,626 bp · p 0.8 · regional, not allelic
Overall
CADD	19.51	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 0.0495% Middle Eastern · 3/6,058 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.000991% 16/1,614,032 alleles · ultra-rare exomes 13/1,461,878 · genomes 3/152,154 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
African / African-American	0.00267%	37,496
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	0.000847%	118,001

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: NASP
Protein: p.Pro314Ser
Coding: c.940C>T
MANE Select: NM_002482
dbSNP: rs759459986
Type: single nucleotide variant
Location: chr1:45607851 (GRCh38)
Gene constraint: LOEUF 0.394 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 5 PDB
Residue 314: the 'disordered' region

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

Similar variants

NASP p.Pro195= Benign ★★ same type
NASP p.Ala18Asp Uncertain significance ★ ⚠ same type
NASP p.Ala18Pro Uncertain significance ★ ⚠ same type
NASP p.Ala217Val Uncertain significance ★ ⚠ same type
NASP p.Ala328Gly Uncertain significance ★ ⚠ same type
NASP p.Ala354Gly Uncertain significance ★ ⚠ same type
NASP p.Ala356Gly Uncertain significance ★ ⚠ same type
NASP p.Ala542Thr 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/nasp-p-pro314ser (accessed [today's date]).

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