Is AMD1 p.Thr238Ile (c.713C>T) pathogenic?

AMD1 p.Thr238Ile (c.713C>T) is classified Uncertain significance in AMD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-20). AlphaMissense: ambiguous (0.394); Very rare (popmax 0.00331%, nfe).

How common is AMD1 p.Thr238Ile (c.713C>T) in the general population?

AMD1 p.Thr238Ile (c.713C>T) is very rare (popmax 0.00331%, nfe) (gnomAD).

What do computational predictors say about AMD1 p.Thr238Ile (c.713C>T)?

AlphaMissense predicts ambiguous (score 0.394) — an in-silico prediction, not a clinical call.

AMD1 p.Thr238Ile

c.713C>T · rs146968037 · VCV2361178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.394 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Computational evidence

Protein change
AlphaMissense	0.394	ambiguous
REVEL	0.359	indeterminate
SaProt	LLR -7.57	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 4,672 bp · p 1.3e-09 · regional, not allelic
Overall
CADD	21.7	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 0.00331% European (non-Finnish) · 39/1,180,000 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00248% 40/1,613,856 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00331%	30,256
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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: AMD1
Protein: p.Thr238Ile
Coding: c.713C>T
MANE Select: NM_001634
dbSNP: rs146968037
Type: single nucleotide variant
Location: chr6:110892914 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 93.52 · 28 PDB

Full AMD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK19 p.Thr31Asn Pathogenic/Likely pathogenic ★★ same type
CDK19 p.Gly28Ala Likely pathogenic ★ same type
CDK19 p.Gly28Arg Pathogenic ★ same type
CDK19 p.Tyr32His Pathogenic ★ same type
AMD1 p.Arg168Gln Uncertain significance ★ ⚠ same type
AMD1 p.Arg210Cys Uncertain significance ★ ⚠ same type
AMD1 p.Arg210His Uncertain significance ★ ⚠ same type
AMD1 p.Arg269Gly 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/amd1-p-thr238ile (accessed [today's date]).

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