Is NEFH p.Phe205= (c.615C>T) pathogenic?

NEFH p.Phe205= (c.615C>T) is classified Likely benign in NEFH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-01). Very rare (popmax 0.00118%, nfe).

How common is NEFH p.Phe205= (c.615C>T) in the general population?

NEFH p.Phe205= (c.615C>T) is very rare (popmax 0.00118%, nfe) (gnomAD).

NEFH p.Phe205=

c.615C>T · VCV3627038

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00118%, nfe)

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 0.093	GERP -1.5, phastCons 0.96
Overall
CADD	13.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00118% European (non-Finnish) · 13/1,098,928 alleles

Filtering AF 0.00066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000509%

Overall 0.000917% 13/1,417,596 alleles · very rare exomes 7/1,265,634 · genomes 6/151,962 · joint denominator

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.Phe205=
Coding: c.615C>T
MANE Select: NM_021076
Type: single nucleotide variant
Location: chr22:29480877 (GRCh38)
Gene constraint: LOEUF 1.417 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 205: the if rod domain; the 'coil 1b' 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-phe205 (accessed [today's date]).

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