Is NDNF p.Ser464= (c.1392A>G) pathogenic?

NDNF p.Ser464= (c.1392A>G) is classified Benign in NDNF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-05). Common (popmax 95.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hypogonadotropic hypogonadism 25 with anosmia.

What condition is associated with NDNF p.Ser464= (c.1392A>G)?

NDNF p.Ser464= (c.1392A>G) is associated with hypogonadotropic hypogonadism 25 with anosmia (ClinVar).

NDNF p.Ser464=

Q: How common is NDNF p.Ser464= (c.1392A>G) in the general population?

NDNF p.Ser464= (c.1392A>G) is common (popmax 95.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1392A>G · rs1397645 · VCV1321859

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 95.3%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

hypogonadotropic hypogonadism 25 with anosmia

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 -4.4
Overall
CADD	0.011	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 95.3% East Asian · 42,779/44,876 alleles

Filtering AF 94.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 94.3%

Overall 86.5% 1,396,483/1,614,000 alleles · common exomes 1,271,530/1,461,838 · genomes 124,953/152,162 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	95.3%	1
Finnishnot grpmax-eligible	91.4%	1
Admixed American	90.4%	1
South Asian	87.4%	1
European (non-Finnish)	87.1%	1
Remaining individualsnot grpmax-eligible	85.7%	1
Ashkenazi Jewishnot grpmax-eligible	80.5%	1
Amishnot grpmax-eligible	78.7%	1
Middle Eastern	78.2%	1
African / African-American	67.3%	1

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: NDNF
Protein: p.Ser464=
Coding: c.1392A>G
MANE Select: NM_024574
dbSNP: rs1397645
Type: single nucleotide variant
Location: chr4:121036579 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 78.58
Residue 464: the fibronectin type-iii 2 domain; a UniProt-annotated variant site (in hh25; loss of protein expression)

Full NDNF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism 25 with anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NDNF p.Lys275Asn Uncertain significance ★★ ⚠ same condition
NDNF p.Lys341Glu Uncertain significance ★★ ⚠ same condition
NDNF p.Asp313= Benign ★★ same condition
NDNF p.Leu145= Benign ★★ same condition
NDNF p.Leu345= Benign ★★ same condition
NDNF p.Leu523= Benign ★★ same condition
NDNF p.Lys62= Benign ★★ same condition
NDNF p.Lys62Ter Pathogenic same condition

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/ndnf-p-ser464 (accessed [today's date]).

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