Is NEB p.Pro653Ser (c.1957C>T) pathogenic?

NEB p.Pro653Ser (c.1957C>T) is classified Conflicting classifications of pathogenicity in NEB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-16). AlphaMissense: ambiguous (0.5465); Very rare (popmax 0.0017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NEB p.Pro653Ser (c.1957C>T)?

NEB p.Pro653Ser (c.1957C>T) is associated with Inborn genetic diseases, nemaline myopathy 2 (ClinVar).

How common is NEB p.Pro653Ser (c.1957C>T) in the general population?

NEB p.Pro653Ser (c.1957C>T) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about NEB p.Pro653Ser (c.1957C>T)?

AlphaMissense predicts ambiguous (score 0.5465) — an in-silico prediction, not a clinical call.

NEB p.Pro653Ser

c.1957C>T · rs759215923 · VCV645953

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5465	ambiguous
REVEL	0.291	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 82 kb · p 0.26 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0017% European (non-Finnish) · 20/1,179,794 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00124% 20/1,613,624 alleles · very rare exomes 18/1,461,502 · genomes 2/152,122 · joint denominator

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: NEB
Protein: p.Pro653Ser
Coding: c.1957C>T
MANE Select: NM_001164508
dbSNP: rs759215923
Type: single nucleotide variant
Location: chr2:151692302 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nemaline myopathy 2

Similar variants

NEB p.Pro653Ala Uncertain significance ★ ⚠ same residue
NEB c.11910+1G>A Likely pathogenic ★★★ same condition
NEB c.6076-1G>T Likely pathogenic ★★★ same condition
NEB c.78+1G>A Pathogenic ★★★ same condition
NEB p.Arg2313Ter Pathogenic ★★★ same condition
NEB p.Asp498Gly Likely pathogenic ★★★ ⚠ same condition
NEB p.Ser6366Ile Pathogenic ★★★ same condition
NEB p.Ser6648= Pathogenic ★★★ same condition

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/neb-p-pro653ser (accessed [today's date]).

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