Is NEB p.Ser2912Pro (c.8734T>C) pathogenic?

NEB p.Ser2912Pro (c.8734T>C) is classified Benign in NEB (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0312); Common (popmax 63.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with nemaline myopathy 2.

What condition is associated with NEB p.Ser2912Pro (c.8734T>C)?

NEB p.Ser2912Pro (c.8734T>C) is associated with nemaline myopathy 2, arthrogryposis multiplex congenita 6 (ClinVar).

How is Severe congenital nemaline myopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NEB p.Ser2912Pro (c.8734T>C)?

AlphaMissense predicts likely benign (score 0.0312) — an in-silico prediction, not a clinical call.

NEB p.Ser2912Pro

Q: How common is NEB p.Ser2912Pro (c.8734T>C) in the general population?

NEB p.Ser2912Pro (c.8734T>C) is common (popmax 63.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.8734T>C · rs6713162 · VCV129761

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0312 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 63.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

nemaline myopathy 2

Computational evidence

Protein change
AlphaMissense	0.0312	likely benign
REVEL	0.11	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 10	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 37 kb · p 2.1e-05 · 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 63.8% African / African-American · 47,822/74,930 alleles

Filtering AF 63.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 63.1%

Overall 20.7% 333,664/1,613,564 alleles · common exomes 286,005/1,461,466 · genomes 47,659/152,098 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	63.8%	2
East Asian	62%	2
South Asian	33.3%	3
Ashkenazi Jewishnot grpmax-eligible	24.9%	4
Remaining individualsnot grpmax-eligible	24.2%	4
Middle Eastern	22.4%	4
Amishnot grpmax-eligible	17.6%	6
European (non-Finnish)	15.7%	6
Admixed American	15.7%	6
Finnishnot grpmax-eligible	14%	7

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.Ser2912Pro
Coding: c.8734T>C
MANE Select: NM_001164508
dbSNP: rs6713162
Type: single nucleotide variant
Location: chr2:151640012 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 2912: a UniProt-annotated variant site (in amc6); a UniProt-annotated variant site (in)

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

Disease context

nemaline myopathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arthrogryposis multiplex congenita 6

For Severe congenital nemaline myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

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
NEB c.22590+2T>C Uncertain significance ★★★ 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-ser2912pro (accessed [today's date]).

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