Is NDNF p.Pro306Ser (c.916C>T) pathogenic?

NDNF p.Pro306Ser (c.916C>T) is classified Uncertain significance in NDNF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely benign (0.2967); Very rare (popmax 0.000424%, nfe).

How common is NDNF p.Pro306Ser (c.916C>T) in the general population?

NDNF p.Pro306Ser (c.916C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about NDNF p.Pro306Ser (c.916C>T)?

AlphaMissense predicts likely benign (score 0.2967) — an in-silico prediction, not a clinical call.

NDNF p.Pro306Ser

c.916C>T · VCV3918257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2967	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -10.32	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,570 bp · p 0.052 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,012 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,948 alleles · very rare exomes 5/1,461,736 · genomes 0/152,212 · joint denominator

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.Pro306Ser
Coding: c.916C>T
MANE Select: NM_024574
Type: single nucleotide variant
Location: chr4:121037055 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 78.58
Residue 306: the fibronectin type-iii 1 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

Similar variants

NDNF p.Lys275Asn Uncertain significance ★★ ⚠ same type
NDNF p.Lys341Glu Uncertain significance ★★ ⚠ same type
NDNF p.Asp313= Benign ★★ same type
NDNF p.Leu145= Benign ★★ same type
NDNF p.Leu345= Benign ★★ same type
NDNF p.Leu523= Benign ★★ same type
NDNF p.Lys62= Benign ★★ same type
NDNF p.Ser464= Benign ★★ 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/ndnf-p-pro306ser (accessed [today's date]).

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