Is AFDN p.Glu658Gly (c.1973A>G) pathogenic?

AFDN p.Glu658Gly (c.1973A>G) is classified Uncertain significance in AFDN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: ambiguous (0.3746); Ultra-rare (popmax 0.0681%, sas).

How common is AFDN p.Glu658Gly (c.1973A>G) in the general population?

AFDN p.Glu658Gly (c.1973A>G) is ultra-rare (popmax 0.0681%, sas) (gnomAD).

What do computational predictors say about AFDN p.Glu658Gly (c.1973A>G)?

AlphaMissense predicts ambiguous (score 0.3746) — an in-silico prediction, not a clinical call.

AFDN p.Glu658Gly

c.1973A>G · rs148916042 · VCV2356749

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3746 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, sas)

Computational evidence

Protein change
AlphaMissense	0.3746	ambiguous
REVEL	0.503	indeterminate
SaProt	LLR -8.55	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 51 kb · p 1.7e-06 · regional, not allelic
Overall
CADD	25.3	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 0.0681% South Asian · 62/91,070 alleles

Filtering AF 0.0544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0495%

Overall 0.0184% 297/1,613,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.503%	199
South Asiangrpmax	0.0681%	1,469
Remaining individualsnot grpmax-eligible	0.0496%	2,016
European (non-Finnish)	0.00458%	21,852
Admixed American	0.00167%	60,000

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AFDN
Protein: p.Glu658Gly
Coding: c.1973A>G
MANE Select: NM_001386888
dbSNP: rs148916042
Type: single nucleotide variant
Location: chr6:167911425 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.69 · 6 PDB

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

Similar variants

AFDN p.Ile438Val Uncertain significance ★★ ⚠ same type
AFDN c.4968+1G>C Uncertain significance ★ same type
AFDN p.Arg1634Leu Uncertain significance ★ ⚠ same type
AFDN p.Arg1717Ter Uncertain significance ★ same type
AFDN p.Arg999His Uncertain significance ★ ⚠ same type
AFDN p.Asp1176Glu Uncertain significance ★ ⚠ same type
AFDN p.Asp1516Ala Uncertain significance ★ ⚠ same type
AFDN p.Asp539His 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/afdn-p-glu658gly (accessed [today's date]).

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