Is NEFH p.Pro747= (c.2241A>T) pathogenic?

NEFH p.Pro747= (c.2241A>T) is classified Likely benign in NEFH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). Very rare (popmax 0.00114%, sas).

How common is NEFH p.Pro747= (c.2241A>T) in the general population?

NEFH p.Pro747= (c.2241A>T) is very rare (popmax 0.00114%, sas) (gnomAD).

NEFH p.Pro747=

c.2241A>T · rs546363585 · VCV3238999

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00114%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3
Overall
CADD	0.022	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00114% South Asian · 1/87,738 alleles

Overall 0.000128% 2/1,565,652 alleles · very rare exomes 1/1,425,774 · genomes 1/139,878 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00114%	87,738
European (non-Finnish)	8.59e-05%	1,164,816

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: NEFH
Protein: p.Pro747=
Coding: c.2241A>T
MANE Select: NM_021076
dbSNP: rs546363585
Type: single nucleotide variant
Location: chr22:29489881 (GRCh38)
Gene constraint: LOEUF 1.417 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 747: the 'tail' region; the 'disordered' region; the '30 x 6 aa repeats of k-s-p-[aepv]-[eak]-[aevk]' region

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

Similar variants

NEFH p.Pro747Ser Uncertain significance ★★ same residue
NEFH c.1208+4A>T Uncertain significance ★★ same type
NEFH c.1209-2A>G Uncertain significance ★★ same type
NEFH p.Ala103Thr Uncertain significance ★★ same type
NEFH p.Ala141Thr Uncertain significance ★★ same type
NEFH p.Ala189Val Uncertain significance ★★ same type
NEFH p.Ala195Thr Uncertain significance ★★ same type
NEFH p.Ala203Thr Uncertain significance ★★ same type

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/nefh-p-pro747 (accessed [today's date]).

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