Is ADHFE1 p.Arg259Gln (c.776G>A) pathogenic?

ADHFE1 p.Arg259Gln (c.776G>A) is classified Uncertain significance in ADHFE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.1715); Ultra-rare (popmax 0.0117%, amr).

How common is ADHFE1 p.Arg259Gln (c.776G>A) in the general population?

ADHFE1 p.Arg259Gln (c.776G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about ADHFE1 p.Arg259Gln (c.776G>A)?

AlphaMissense predicts likely benign (score 0.1715) — an in-silico prediction, not a clinical call.

ADHFE1 p.Arg259Gln

c.776G>A · rs200761663 · VCV2250261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1715 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1715	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -12.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 36 kb · p 0.69 · regional, not allelic
Overall
CADD	31.0	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 0.0117% Admixed American · 7/60,006 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00285% 46/1,614,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,572
South Asian	0.00549%	18,216
European (non-Finnish)	0.00263%	38,064
East Asian	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,508
African / African-American	0.00133%	75,016

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: ADHFE1
Protein: p.Arg259Gln
Coding: c.776G>A
MANE Select: NM_144650
dbSNP: rs200761663
Type: single nucleotide variant
Location: chr8:66451994 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.00

Full ADHFE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADHFE1 p.Arg259Trp Uncertain significance ★ ⚠ same residue
ADHFE1 p.Ala136Asp Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala233Thr Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala237Thr Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala247Ser Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala271Glu Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala283Ser Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala283Val 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/adhfe1-p-arg259gln (accessed [today's date]).

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