Is NEB p.Phe438Val (c.1312T>G) pathogenic?

NEB p.Phe438Val (c.1312T>G) is classified Uncertain significance in NEB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-02). AlphaMissense: likely benign (0.1956); Very rare (popmax 0.000932%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NEB p.Phe438Val (c.1312T>G)?

NEB p.Phe438Val (c.1312T>G) is associated with Inborn genetic diseases, nemaline myopathy 2 (ClinVar).

How common is NEB p.Phe438Val (c.1312T>G) in the general population?

NEB p.Phe438Val (c.1312T>G) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about NEB p.Phe438Val (c.1312T>G)?

AlphaMissense predicts likely benign (score 0.1956) — an in-silico prediction, not a clinical call.

NEB p.Phe438Val

c.1312T>G · rs959840049 · VCV948214

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1956	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 82 kb · p 0.26 · regional, not allelic
Overall
CADD	18.93	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,179,878 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,613,874 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.Phe438Val
Coding: c.1312T>G
MANE Select: NM_001164508
dbSNP: rs959840049
Type: single nucleotide variant
Location: chr2:151697403 (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.Phe438= Likely benign ★ same residue
NEB p.Phe438Leu 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

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-phe438val (accessed [today's date]).

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