Is NEFH p.Phe4= (c.12C>T) pathogenic?

NEFH p.Phe4= (c.12C>T) is classified Likely benign in NEFH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). Very rare (popmax 0.00433%, afr).

How common is NEFH p.Phe4= (c.12C>T) in the general population?

NEFH p.Phe4= (c.12C>T) is very rare (popmax 0.00433%, afr) (gnomAD).

NEFH p.Phe4=

c.12C>T · rs746957137 · VCV1901194

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00433%, afr)

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 3.7	GERP 1.7, phastCons 1
Overall
CADD	15.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00433% African / African-American · 3/69,232 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00197%

Overall 0.00258% 39/1,510,412 alleles · very rare exomes 32/1,358,188 · genomes 7/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00433%	23,077
European (non-Finnish)	0.00307%	32,525
Admixed American	0.00211%	47,350

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.Phe4=
Coding: c.12C>T
MANE Select: NM_021076
dbSNP: rs746957137
Type: single nucleotide variant
Location: chr22:29480274 (GRCh38)
Gene constraint: LOEUF 1.417 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 4: the 'head' region

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

Similar variants

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
NEFH p.Ala220Val 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-phe4 (accessed [today's date]).

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