Is NEB p.Pro688Ala (c.2062C>G) pathogenic?

NEB p.Pro688Ala (c.2062C>G) is classified Conflicting classifications of pathogenicity in NEB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.2529); Ultra-rare (popmax 0.03%, amr); Associated with Inborn genetic diseases.

What condition is associated with NEB p.Pro688Ala (c.2062C>G)?

NEB p.Pro688Ala (c.2062C>G) is associated with Inborn genetic diseases, nemaline myopathy 2 (ClinVar).

How common is NEB p.Pro688Ala (c.2062C>G) in the general population?

NEB p.Pro688Ala (c.2062C>G) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about NEB p.Pro688Ala (c.2062C>G)?

AlphaMissense predicts likely benign (score 0.2529) — an in-silico prediction, not a clinical call.

NEB p.Pro688Ala

c.2062C>G · rs750276279 · VCV576848

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2529 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2529	likely benign
REVEL	0.191	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 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 82 kb · p 0.26 · regional, not allelic
Overall
CADD	22.9	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 0.03% Admixed American · 18/60,002 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00123% 18/1,461,664 alleles · ultra-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.Pro688Ala
Coding: c.2062C>G
MANE Select: NM_001164508
dbSNP: rs750276279
Type: single nucleotide variant
Location: chr2:151692103 (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.Pro688= Likely benign ★ same residue
NEB p.Pro688Ser 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

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-pro688ala (accessed [today's date]).

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