Is AFDN p.Arg999His (c.2996G>A) pathogenic?

AFDN p.Arg999His (c.2996G>A) is classified Uncertain significance in AFDN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). AlphaMissense: likely benign (0.0733); Ultra-rare (popmax 0.0418%, sas).

How common is AFDN p.Arg999His (c.2996G>A) in the general population?

AFDN p.Arg999His (c.2996G>A) is ultra-rare (popmax 0.0418%, sas) (gnomAD).

What do computational predictors say about AFDN p.Arg999His (c.2996G>A)?

AlphaMissense predicts likely benign (score 0.0733) — an in-silico prediction, not a clinical call.

AFDN p.Arg999His

c.2996G>A · rs759978772 · VCV2237859

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0418%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0733	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -0.28, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 7,527 bp · p 0.13 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R992H vs ClinVar R999H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0418% South Asian · 38/90,894 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.00894% 144/1,611,454 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0418%	2,392
East Asian	0.0268%	3,735
African / African-American	0.0134%	7,484
European (non-Finnish)	0.00662%	15,103
Admixed American	0.00501%	19,957
Remaining individualsnot grpmax-eligible	0.00481%	20,796

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.Arg999His
Coding: c.2996G>A
MANE Select: NM_001386888
dbSNP: rs759978772
Type: single nucleotide variant
Location: chr6:167922943 (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.Asp1176Glu Uncertain significance ★ ⚠ same type
AFDN p.Asp1516Ala Uncertain significance ★ ⚠ same type
AFDN p.Asp539His Uncertain significance ★ ⚠ same type
AFDN p.Gln1217Ter 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-arg999his (accessed [today's date]).

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