Is NEFH p.Pro663= (c.1989T>A) pathogenic?

NEFH p.Pro663= (c.1989T>A) is classified Likely benign in NEFH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0702%, afr).

How common is NEFH p.Pro663= (c.1989T>A) in the general population?

NEFH p.Pro663= (c.1989T>A) is ultra-rare (popmax 0.0702%, afr) (gnomAD).

NEFH p.Pro663=

c.1989T>A · rs367989424 · VCV1536667

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0702%, 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 -20	GERP -3.3
Overall
CADD	0.006	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0702% African / African-American · 23/32,752 alleles

Filtering AF 0.0479% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0407%

Overall 0.00779% 81/1,039,826 alleles · ultra-rare exomes 13/996,312 · genomes 68/43,514 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.427%	234
African / African-Americangrpmax	0.0702%	1,424
Admixed American	0.0247%	4,046
Finnishnot grpmax-eligible	0.00914%	10,935
South Asian	0.00866%	11,552
European (non-Finnish)	0.00489%	20,470
Remaining individualsnot grpmax-eligible	0.00468%	21,370

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro663=
Coding: c.1989T>A
MANE Select: NM_021076
dbSNP: rs367989424
Type: single nucleotide variant
Location: chr22:29489629 (GRCh38)
Gene constraint: LOEUF 1.417 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 663: 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 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-pro663 (accessed [today's date]).

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