Is ADHFE1 p.Arg8Gln (c.23G>A) pathogenic?

ADHFE1 p.Arg8Gln (c.23G>A) is classified Uncertain significance in ADHFE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: ambiguous (0.3743); Very rare (popmax 0.00914%, amr).

How common is ADHFE1 p.Arg8Gln (c.23G>A) in the general population?

ADHFE1 p.Arg8Gln (c.23G>A) is very rare (popmax 0.00914%, amr) (gnomAD).

What do computational predictors say about ADHFE1 p.Arg8Gln (c.23G>A)?

AlphaMissense predicts ambiguous (score 0.3743) — an in-silico prediction, not a clinical call.

ADHFE1 p.Arg8Gln

c.23G>A · VCV4638493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00914%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3743	ambiguous
REVEL	0.054	moderately benign-leaning
SaProt	LLR -7.97	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 4.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 36 kb · p 0.69 · regional, not allelic
Overall
CADD	23.0	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 0.00914% Admixed American · 3/32,820 alleles

Filtering AF 0.00242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00127%

Overall 0.00132% 18/1,359,396 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00914%	10,940
Remaining individualsnot grpmax-eligible	0.00198%	50,622
African / African-American	0.0015%	66,760
European (non-Finnish)	0.00124%	80,388

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.Arg8Gln
Coding: c.23G>A
MANE Select: NM_144650
Type: single nucleotide variant
Location: chr8:66432539 (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.Arg8Trp 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-arg8gln (accessed [today's date]).

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