Is NEFH p.Arg231= (c.693G>A) pathogenic?

NEFH p.Arg231= (c.693G>A) is classified Likely benign in NEFH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). Ultra-rare (popmax 0.018%, afr).

How common is NEFH p.Arg231= (c.693G>A) in the general population?

NEFH p.Arg231= (c.693G>A) is ultra-rare (popmax 0.018%, afr) (gnomAD).

NEFH p.Arg231=

c.693G>A · rs926329788 · VCV1611656

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, 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 2.1	GERP -4.4, phastCons 1
Overall
CADD	17.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.018% African / African-American · 13/72,062 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00842%

Overall 0.00098% 15/1,530,280 alleles · ultra-rare exomes 11/1,378,112 · genomes 4/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.018%	5,543
South Asian	0.00119%	83,746
European (non-Finnish)	8.73e-05%	1,145,162

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.Arg231=
Coding: c.693G>A
MANE Select: NM_021076
dbSNP: rs926329788
Type: single nucleotide variant
Location: chr22:29480955 (GRCh38)
Gene constraint: LOEUF 1.417 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.28
Residue 231: 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 p.Arg231Gly 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-arg231 (accessed [today's date]).

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