Is NEFH p.Ala554Pro (c.1660G>C) pathogenic?

NEFH p.Ala554Pro (c.1660G>C) is classified Uncertain significance in NEFH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-30). Absent from gnomAD v4.1.

How common is NEFH p.Ala554Pro (c.1660G>C) in the general population?

NEFH p.Ala554Pro (c.1660G>C) is absent from gnomAD v4.1 (gnomAD).

NEFH p.Ala554Pro

c.1660G>C · rs2063062645 · VCV2752292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.212	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.04	GERP -1
Regional constraint	o/e 0.81	unconstrained · MANE · 3,773 bp · p 0.0012 · regional, not allelic
Overall
CADD	7.701	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NEFH
Protein: p.Ala554Pro
Coding: c.1660G>C
MANE Select: NM_021076
dbSNP: rs2063062645
Type: single nucleotide variant
Location: chr22:29489300 (GRCh38)
Gene constraint: LOEUF 1.417 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 554: 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.Ala554_Pro567del Conflicting classifications of pathogenicity ★ 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-ala554pro (accessed [today's date]).

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