Is NEFH p.Ser511= (c.1533C>T) pathogenic?

NEFH p.Ser511= (c.1533C>T) is classified Likely benign in NEFH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-04). Ultra-rare (popmax 0.0227%, afr).

How common is NEFH p.Ser511= (c.1533C>T) in the general population?

NEFH p.Ser511= (c.1533C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

NEFH p.Ser511=

c.1533C>T · rs766285926 · VCV1945213

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, 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 -0.8	GERP -4.4, phastCons 0.018
Overall
CADD	4.079	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/74,924 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00124% 20/1,613,952 alleles · ultra-rare exomes 8/1,461,752 · genomes 12/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,407
Admixed American	0.005%	19,991

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.Ser511=
Coding: c.1533C>T
MANE Select: NM_021076
dbSNP: rs766285926
Type: single nucleotide variant
Location: chr22:29489173 (GRCh38)
Gene constraint: LOEUF 1.417 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 511: the 'tail' region; the 'disordered' region; a modified residue (phosphoserine)

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-ser511 (accessed [today's date]).

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