Is ADAM29 p.His751Gln (c.2253T>A) pathogenic?

ADAM29 p.His751Gln (c.2253T>A) is classified Likely benign in ADAM29 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely benign (0.0788); Ultra-rare (popmax 0.0355%, afr).

How common is ADAM29 p.His751Gln (c.2253T>A) in the general population?

ADAM29 p.His751Gln (c.2253T>A) is ultra-rare (popmax 0.0355%, afr) (gnomAD).

What do computational predictors say about ADAM29 p.His751Gln (c.2253T>A)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

ADAM29 p.His751Gln

c.2253T>A · VCV3828665

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0355%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -5.14	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 -2.2	GERP -0.63
Regional constraint	o/e 0.97	unconstrained · MANE · 2,459 bp · p 0.3 · regional, not allelic
Overall
CADD	0.048	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 0.0355% African / African-American · 23/64,808 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00435% 68/1,562,230 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.15%	666
African / African-Americangrpmax	0.0355%	2,818
Admixed American	0.0141%	7,088
East Asian	0.00694%	14,415
Finnishnot grpmax-eligible	0.00653%	15,323
Remaining individualsnot grpmax-eligible	0.00492%	20,335
South Asian	0.00449%	22,260
European (non-Finnish)	0.00191%	52,338

Amish 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: ADAM29
Protein: p.His751Gln
Coding: c.2253T>A
MANE Select: NM_014269
Type: single nucleotide variant
Location: chr4:174977778 (GRCh38)
Gene constraint: LOEUF 1.939 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.07
Residue 751: the 'disordered' region; the '9 x 9 aa approximate repeats' region

Full ADAM29 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM29 p.Ala314Glu Uncertain significance ★ ⚠ same type
ADAM29 p.Ala88Val Uncertain significance ★ ⚠ same type
ADAM29 p.Arg213Cys Uncertain significance ★ ⚠ same type
ADAM29 p.Arg311His Uncertain significance ★ ⚠ same type
ADAM29 p.Arg501His Uncertain significance ★ ⚠ same type
ADAM29 p.Arg530Cys Uncertain significance ★ ⚠ same type
ADAM29 p.Arg723Cys Uncertain significance ★ ⚠ same type
ADAM29 p.Arg804Thr 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/adam29-p-his751gln (accessed [today's date]).

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