Is NEFH p.Pro655= (c.1965A>T) pathogenic?

NEFH p.Pro655= (c.1965A>T) is classified Likely benign in NEFH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Low-frequency (popmax 1.3%, afr).

How common is NEFH p.Pro655= (c.1965A>T) in the general population?

NEFH p.Pro655= (c.1965A>T) is low-frequency (popmax 1.3%, afr) (gnomAD).

NEFH p.Pro655=

c.1965A>T · rs79235463 · VCV1253861

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.3%, 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 -3.2
Overall
CADD	0.031	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.3% African / African-American · 236/18,156 alleles

Filtering AF 1.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.11%

Overall 0.204% 895/437,774 alleles · low-frequency exomes 57/404,328 · genomes 838/33,446 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	3.37%	30
African / African-Americangrpmax	1.3%	77
Admixed American	0.406%	247
Middle Eastern	0.235%	426
Ashkenazi Jewishnot grpmax-eligible	0.231%	433
Finnishnot grpmax-eligible	0.202%	495
East Asian	0.172%	580
South Asian	0.165%	605
European (non-Finnish)	0.138%	727
Remaining individualsnot grpmax-eligible	0.0794%	1,259

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.Pro655=
Coding: c.1965A>T
MANE Select: NM_021076
dbSNP: rs79235463
Type: single nucleotide variant
Location: chr22:29489605 (GRCh38)
Gene constraint: LOEUF 1.417 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 655: 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.Pro655_Glu656insValLysGluGluAlaLysSerProGluLysAlaLysSerProGluLysAlaLysSerPro 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-pro655 (accessed [today's date]).

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