Is NGFR p.Pro166Ser (c.496C>T) pathogenic?

NGFR p.Pro166Ser (c.496C>T) is classified Uncertain significance in NGFR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely pathogenic (0.969); Very rare (popmax 0.00263%, nfe).

How common is NGFR p.Pro166Ser (c.496C>T) in the general population?

NGFR p.Pro166Ser (c.496C>T) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about NGFR p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely pathogenic (score 0.969) — an in-silico prediction, not a clinical call.

NGFR p.Pro166Ser

c.496C>T · VCV3405337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.969	likely pathogenic
REVEL	0.724	pathogenic-leaning
SaProt	LLR -13.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 18 kb · p 0.0027 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% European (non-Finnish) · 31/1,178,958 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00193% 31/1,610,198 alleles · very rare exomes 31/1,458,130 · genomes 0/152,068 · 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: NGFR
Protein: p.Pro166Ser
Coding: c.496C>T
MANE Select: NM_002507
Type: single nucleotide variant
Location: chr17:49506586 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.44 · 7 PDB

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

Similar variants

NGFR c.67-4C>T Benign ★★ same type
NGFR p.Ser132Leu Benign ★★ same type
NGFR p.Ser395= Benign/Likely benign ★★ same type
NGFR p.Thr293= Benign ★★ same type
NGFR p.Tyr111= Benign ★★ same type
NGFR p.Ala110Ser Uncertain significance ★ ⚠ same type
NGFR p.Ala229Val Uncertain significance ★ ⚠ same type
NGFR p.Ala28Asp 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/ngfr-p-pro166ser (accessed [today's date]).

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