Is ADHFE1 p.Asp67His (c.199G>C) pathogenic?

ADHFE1 p.Asp67His (c.199G>C) is classified Uncertain significance in ADHFE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.922); Very rare (popmax 0.00267%, afr).

How common is ADHFE1 p.Asp67His (c.199G>C) in the general population?

ADHFE1 p.Asp67His (c.199G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ADHFE1 p.Asp67His (c.199G>C)?

AlphaMissense predicts likely pathogenic (score 0.922) — an in-silico prediction, not a clinical call.

ADHFE1 p.Asp67His

c.199G>C · VCV4244181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.922 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.922	likely pathogenic · top 4% in ADHFE1
REVEL	0.622	indeterminate
SaProt	LLR -13.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.22	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.42	loss · gain 0.25 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.3	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 36 kb · p 0.69 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,880 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00192% 31/1,613,852 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,440
European (non-Finnish)	0.00237%	42,143
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Asp67His
Coding: c.199G>C
MANE Select: NM_144650
Type: single nucleotide variant
Location: chr8:66444594 (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.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
ADHFE1 p.Ala286Glu 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-asp67his (accessed [today's date]).

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