Is AFTPH p.Ile612Thr (c.1835T>C) pathogenic?

AFTPH p.Ile612Thr (c.1835T>C) is classified Uncertain significance in AFTPH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.0537); Very rare (popmax 8.47e-05%, nfe).

How common is AFTPH p.Ile612Thr (c.1835T>C) in the general population?

AFTPH p.Ile612Thr (c.1835T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AFTPH p.Ile612Thr (c.1835T>C)?

AlphaMissense predicts likely benign (score 0.0537) — an in-silico prediction, not a clinical call.

AFTPH p.Ile612Thr

c.1835T>C · rs370571980 · VCV3093417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0537	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -5.83	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 -0.65	GERP -4
Overall
CADD	1.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 0.00062% 10/1,614,004 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,672
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)grpmax	8.47e-05%	1,180,020

Finnish 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: AFTPH
Protein: p.Ile612Thr
Coding: c.1835T>C
MANE Select: NM_203437
dbSNP: rs370571980
Type: single nucleotide variant
Location: chr2:64553309 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 46.36
Residue 612: the 'disordered' region

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-ile612thr (accessed [today's date]).

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