Is NEB p.Ser3271Phe (c.9812C>T) pathogenic?

NEB p.Ser3271Phe (c.9812C>T) is classified Conflicting classifications of pathogenicity in NEB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-17). AlphaMissense: likely pathogenic (0.6021); Very rare (popmax 8.48e-05%, nfe); Associated with nemaline myopathy.

What condition is associated with NEB p.Ser3271Phe (c.9812C>T)?

NEB p.Ser3271Phe (c.9812C>T) is associated with nemaline myopathy, nemaline myopathy 2 (ClinVar).

How common is NEB p.Ser3271Phe (c.9812C>T) in the general population?

NEB p.Ser3271Phe (c.9812C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about NEB p.Ser3271Phe (c.9812C>T)?

AlphaMissense predicts likely pathogenic (score 0.6021) — an in-silico prediction, not a clinical call.

NEB p.Ser3271Phe

c.9812C>T · rs1192458685 · VCV2434241

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6021 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

nemaline myopathy

Computational evidence

Protein change
AlphaMissense	0.6021	likely pathogenic
REVEL	0.369	indeterminate
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 0.90	unconstrained · MANE · 37 kb · p 2.1e-05 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S3028F vs ClinVar S3271F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,632 alleles

Overall 6.84e-05% 1/1,461,366 alleles · very rare

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.Ser3271Phe
Coding: c.9812C>T
MANE Select: NM_001164508
dbSNP: rs1192458685
Type: single nucleotide variant
Location: chr2:151629558 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 3271: a UniProt-annotated variant site (in amc6)

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

Disease context

nemaline myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nemaline myopathy 2

Similar variants

NEB p.Ser3271= Likely benign ★ 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-ser3271phe (accessed [today's date]).

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