Is ASGR2 p.Phe5Cys (c.14T>G) pathogenic?

ASGR2 p.Phe5Cys (c.14T>G) is classified Uncertain significance in ASGR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.3915); Very rare (popmax 0.0022%, nfe).

How common is ASGR2 p.Phe5Cys (c.14T>G) in the general population?

ASGR2 p.Phe5Cys (c.14T>G) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about ASGR2 p.Phe5Cys (c.14T>G)?

AlphaMissense predicts ambiguous (score 0.3915) — an in-silico prediction, not a clinical call.

ASGR2 p.Phe5Cys

c.14T>G · VCV4153905

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3915	ambiguous
REVEL	0.049	moderately benign-leaning
SaProt	LLR -7.34	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -3, phastCons 0.14
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.94 · regional, not allelic
Overall
CADD	21.4	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 0.0022% European (non-Finnish) · 26/1,180,032 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,613,952 alleles · very rare

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: ASGR2
Protein: p.Phe5Cys
Coding: c.14T>G
MANE Select: NM_001201352
Type: single nucleotide variant
Location: chr17:7114227 (GRCh38)
Gene constraint: LOEUF 1.365 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.50 · 1 PDB
Residue 5: the 'disordered' region

Full ASGR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASGR2 p.Gly303= Benign ★★ same type
ASGR2 p.Thr302= Benign ★★ same type
ASGR2 c.241+11C>A Uncertain significance ★ ⚠ same type
ASGR2 p.Ala108Pro Uncertain significance ★ ⚠ same type
ASGR2 p.Ala108Thr Uncertain significance ★ ⚠ same type
ASGR2 p.Arg153Cys Uncertain significance ★ ⚠ same type
ASGR2 p.Arg169Lys Uncertain significance ★ ⚠ same type
ASGR2 p.Arg248Lys 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/asgr2-p-phe5cys (accessed [today's date]).

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