Is AFTPH p.Thr735Ile (c.2204C>T) pathogenic?

AFTPH p.Thr735Ile (c.2204C>T) is classified Uncertain significance in AFTPH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: ambiguous (0.3778); Ultra-rare (popmax 0.0187%, afr).

How common is AFTPH p.Thr735Ile (c.2204C>T) in the general population?

AFTPH p.Thr735Ile (c.2204C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about AFTPH p.Thr735Ile (c.2204C>T)?

AlphaMissense predicts ambiguous (score 0.3778) — an in-silico prediction, not a clinical call.

AFTPH p.Thr735Ile

c.2204C>T · rs868261565 · VCV2378022

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3778 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Computational evidence

Protein change
AlphaMissense	0.3778	ambiguous
REVEL	0.42	indeterminate
SaProt	LLR -7.68	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Overall
CADD	27.3	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 0.0187% African / African-American · 14/74,816 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00906%

Overall 0.00093% 15/1,612,166 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,344
Remaining individualsnot grpmax-eligible	0.0016%	62,394

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: AFTPH
Protein: p.Thr735Ile
Coding: c.2204C>T
MANE Select: NM_203437
dbSNP: rs868261565
Type: single nucleotide variant
Location: chr2:64569208 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 46.36

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

Similar variants

AFTPH p.Ala204Thr Uncertain significance ★ ⚠ same type
AFTPH p.Ala20Gly Uncertain significance ★ ⚠ same type
AFTPH p.Ala526Gly Uncertain significance ★ ⚠ same type
AFTPH p.Ala587Thr Uncertain significance ★ ⚠ same type
AFTPH p.Ala658Thr Uncertain significance ★ ⚠ same type
AFTPH p.Ala905Thr Uncertain significance ★ ⚠ same type
AFTPH p.Arg256Thr Uncertain significance ★ ⚠ same type
AFTPH p.Arg262Trp 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/aftph-p-thr735ile (accessed [today's date]).

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