Is NEFH p.Phe47= (c.141C>T) pathogenic?

NEFH p.Phe47= (c.141C>T) is classified Conflicting classifications of pathogenicity in NEFH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-22). Very rare (popmax 0.00832%, sas).

How common is NEFH p.Phe47= (c.141C>T) in the general population?

NEFH p.Phe47= (c.141C>T) is very rare (popmax 0.00832%, sas) (gnomAD).

NEFH p.Phe47=

c.141C>T · rs780966618 · VCV809341

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00832%, 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 2	GERP -0.16, phastCons 1
Overall
CADD	14.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00832% South Asian · 7/84,118 alleles

Filtering AF 0.00385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00338%

Overall 0.00449% 69/1,535,578 alleles · very rare exomes 62/1,383,518 · genomes 7/152,060 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00832%	12,017
European (non-Finnish)	0.00479%	20,873
Admixed American	0.00391%	25,591
Remaining individualsnot grpmax-eligible	0.00334%	29,903
African / African-American	0.00274%	36,459
Finnishnot grpmax-eligible	0.00226%	44,280

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.Phe47=
Coding: c.141C>T
MANE Select: NM_021076
dbSNP: rs780966618
Type: single nucleotide variant
Location: chr22:29480403 (GRCh38)
Gene constraint: LOEUF 1.417 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 47: the 'head' region

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

Similar variants

NEFH p.Phe47Leu 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-phe47 (accessed [today's date]).

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